Paclitaxel drug may promote cancer spread at low doses

In continuation of my update on paclitaxel

New research indicates that paclitaxel, which is the most commonly used chemotherapy for breast cancer, suppresses tumors when given at a certain dosage, but at low doses, it actually promotes cancer spread to the liver.

The findings suggest that lowering the dose of paclitaxel to reduce toxic side-effects is not a safe strategy.

"Paclitaxel and its analogous compounds are the first line agents widely used in clinical cancer chemotherapy. However, potential risks and reasonable treatment strategies of paclitaxel continue to be widely investigated," wrote the authors of The FEBS Journalstudy.

http://onlinelibrary.wiley.com/doi/10.1111/febs.13767/full

Increase in EPA/DHA omega-3 intake linked to lower risk of all-cause mortality

A recent meta-analysis in Scientific Reports supports a link between EPA and DHA omega-3 intake and a reduced risk of death by any cause. The meta-analysis included 11 studies involving 371,965 participants and 31,185 death events, with a subset of the studies being used for different analyses.

DHA   EPA

In the analysis of n-3 LCPUFA intake, there was a 9% reduced risk of all-cause death associated with high versus low omega-3 intake. In the dose-response analysis, an increase in EPA/DHA intake of 300 mg/day was associated with a 6% lower risk of all-cause mortality. These findings suggest that both dietary and circulating n-3 LCPUFA are shown to be significantly associated with reduced risk of all-cause mortality.

According to study author Manfred Eggersdorfer, "The meta-analysis of 11 prospective observational studies demonstrates that each 1% increment of omega-3s in total fatty acids in blood may be associated with a 20% decrease in risk of all-cause mortality. This is an important finding for the potential contribution of adequate omega-3 intake to public health."

Novel combination therapy shows strong response in phase 1 trial

In continuation of my update on Sorafenib, Premetrexed,  Vandetanib
"Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial," said Andrew Poklepovic, M.D., lead investigator on the study. "With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study."

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

"Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable," says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

 Sorafenib  Pemetrexed

  Vandetanib    Lapatinib

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best "third drug" that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

"We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer," says Dent. "Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors."

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

"Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy," says Dent. "We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data."

The multiplex assay provided Dent's team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

"The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular 'fingerprint' of the point at which tumors develop resistance to the therapy," says Dent. "Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient's tumor."

Ref : http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=9434

More reasons to eat your broccoli

In continuation of my update on broccoli

University of Illinois researchers have identified candidate genes controlling the accumulation of phenolic compounds in broccoli. Consumption of phenolic compounds, including certain flavonoids, is associated with a lower risk of coronary heart disease, type II diabetes, asthma, and several types of cancer.

"Phenolic compounds have good antioxidant activity, and there is increasing evidence that this antioxidant activity affects biochemical pathways affiliated with inflammation in mammals. We need inflammation because it's a response to disease or damage, but it's also associated with initiation of a number of degenerative diseases. People whose diets consist of a certain level of these compounds will have a lesser risk of contracting these diseases," explains U of I geneticist Jack Juvik.

The researchers crossed two broccoli lines and tested their progeny in terms of total phenolic content and their ability to neutralize oxygen radicals in cellular assays. They then used a genetic technique called quantitative trait locus analysis to search for the genes involved in generating phenolics in the most promising progeny.

By identifying the genes involved in accumulating these compounds, the researchers are one step closer to breeding broccoli and related Brassica vegetables like kale and cabbage with mega-doses of phenolic compounds.

"It's going to take awhile," Juvik notes. "This work is a step in that direction, but is not the final answer. We plan to take the candidate genes we identified here and use them in a breeding program to improve the health benefits of these vegetables. Meanwhile, we'll have to make sure yield, appearance, and taste are maintained as well."

The good news is that phenolic compounds are flavorless and stable, meaning the vegetables can be cooked without losing health-promoting qualities.

Once these vegetables are consumed, the phenolic compounds are absorbed and targeted to certain areas of the body or concentrated in the liver. Flavonoids spread through the bloodstream, reducing inflammation through their antioxidant activity.

"These are things we can't make ourselves, so we have to get them from our diets," Juvik says. "The compounds don't stick around forever, so we need to eat broccoli or some other Brassica vegetable every three or four days to lower the risk of cancers and other degenerative diseases."

Compound shown to reduce brain damage caused by anesthesia in early study

An experimental drug prevented learning deficits in young mice exposed repeatedly to anesthesia, according to a study led by researchers from NYU Langone Medical Center and published June 22 in Science Translational Medicine.

The study results may have implications for children who must have several surgeries, and so are exposed repeatedly to general anesthesia. Past studies have linked such exposure to a higher incidence of learning disabilities, attention deficits and hyperactivity.

 CX546

Specifically, the research team found that the experimental drug CX546, part of the AMPAkine class in clinical trials for several neurological conditions, counters for the dampening effect of anesthesia on nerve signaling. The treatment bolstered nerve cell activity as well as learning ability in mice recovering from repeated exposure to general anesthesia.

"Each year, in the United States alone, more than a million children under age four undergo surgical procedures that require anesthesia, and the numbers are growing," says the study's senior investigator Guang Yang, PhD, assistant professor of anesthesiology at NYU Langone. "There are currently no effective treatments to combat potential toxicity linked to repeated anesthesia, and we would like to change that."

Yang's group took advantage of genetically engineered young mice that have protein markers which glow in response to changes in nerve function. Researchers then used advanced microscopy to visualize activity in their brains, comparing nerve signaling activity in those exposed to anesthesia to those who were not.

The research team found that anesthesia exposure resulted in a prolonged reduction of signal transmission among nerve cells following anesthesia. They also observed that CX546 treatment enhances this transmission, along with learning and memory in mice exposed to anesthesia.

The team studied the anesthetic ketamine, which blocks NMDA (N-methyl-D-aspartate) receptor proteins that enable charged particles like calcium to flow into nerve cells, like electric switches that trigger and shape messages. In contrast, CX546 increases nerve cell activity and calcium influx into nerve cells by enhancing the activity of proteins called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors.

"We were able to counter anesthesia-induced deficits in the formation of connections between nerve cells and related learning problems," says Yang. "This work is an important proof-of-principle study, and opens the door to a new direction for preventing long-term neurocognitive deficits."

Ref : http://stm.sciencemag.org/content/8/344/344ra85 

Compound shown to reduce brain damage caused by anesthesia in early study  

Painkiller That Killed Prince Part of Dangerous Wave of New Synthetic Drugs

In continuation of my update fentanyl

The recent overdose death of rock legend Prince has brought renewed focus on the dangers posed by synthetic opioids -- laboratory-created narcotics tweaked by chemists to produce potentially lethal highs while skirting U.S. drug laws.

 

Prince Rogers Nelson, 57, died April 21 from an overdose of fentanyl, a drug often used to quell pain in cancer patients when traditional opioids prove ineffective.

Despite its legitimate medical uses, fentanyl has acquired a growing reputation as a dangerous street drug thanks to at least a dozen synthetic variants now available to users, according to the U.S. Drug Enforcement Administration (DEA).

And fentanyl is only one of numerous synthetic opioids and designer drugs now flooding the illicit drug market in the United States, DEA acting chief Chuck Rosenberg warned during a U.S. Senate hearing last week.

"We are trying to keep up with a picture that changes almost every day," Rosenberg testified. "We've identified something like 400 new psychoactive substances over the last four or five years."

Another synthetic opioid, U-47700, has been connected to at least 50 deaths nationwide, but is so new to the black market that the DEA has not yet moved to control it, according to the Associated Press.

 U-47700

Synthetic narcotics are dangerous because their potency can far outstrip traditional opioids. For example, fentanyl is 25 to 40 times more potent than heroin, and 50 to 100 times more potent than morphine, said Dr. Mitra Ahadpour. She is a medical officer with the Center for Substance Abuse Treatment in the U.S. Substance Abuse and Mental Health Services Administration.

Rosenberg testified that "fentanyl is so dangerous we've had to instruct our agents that if they touch it or inhale it accidentally, they can die."

Several states reported sharp increases in overdose deaths caused by fentanyl and its analogs in 2014, a health advisory from the U.S. Centers for Disease Control and Prevention noted. Ohio reported 514 fentanyl-related deaths in 2014 compared to 92 in 2013, while Maryland had 185 fentanyl deaths in 2014 compared to 58 the year before.

Ahadpour explained that "if someone is not opioid-tolerant, and uses either pharmaceutical or illicit fentanyl, you have a very high increased chance of respiratory depression and dying. Their breathing slows down, it goes to shallow breathing, and then they stop breathing."

There's wide variation in the potency of these synthetic drugs, and often they are cut with other illicit drugs, Ahadpour added. A user might buy heroin not knowing that it has been cut with fentanyl to increase its potency.

Eleanor Artigiani, deputy director of policy and governmental affairs with the University of Maryland's Center for Substance Abuse Research, said, "They may think they're getting heroin, or they're just buying a Xanax pill off the street, when it's actually one of these other substances."

Artigiani added, "From what I've been hearing recently, sometimes even the people selling these drugs don't know exactly what's in them either. It's like Russian roulette, because you don't really know what you're getting or what effect it's going to have on you."

Toxicology tests concluded that Prince died from a fentanyl overdose, although the medical examiner's report did not say whether the fentanyl was prescription or an illicit analog, CNN reported.

Designer drugs are typically based on medications that have been around for decades, Artigiani said.

Fentanyl was first created in Belgium in the late 1950s, the DEA says, while U-47700 was developed in the 1970s by the pharmaceutical company Upjohn as a potential alternative for morphine.

Black market drug makers come across the formula for a drug, and then tweak the molecule slightly so that it has the same effect on people but isn't technically the same substance, Artigiani explained.

"There's a journal article or a patent document or something that gets produced," she said. "Illicit chemists find it and reproduce it or tweak the molecules to look for other kinds of things that aren't illegal, that haven't been scheduled yet."

Other synthetic opioids on the streets include substances with names like W-18, AH-7921 and MT-45, according to Congressional testimony provided by James Hall, an epidemiologist with the Center for Applied Research on Substance Use and Health Disparities at Nova Southeastern University in Miami.

Illicit drug manufacturers also produce other categories of designer drugs besides synthetic opioids, Hall said, including synthetic versions of cannabinoids, stimulants and hallucinogens.

Nearly all synthetic opioids and other designer drugs are manufactured in China, U.S. National Drug Control Policy Director Michael Botticelli testified before the Senate.

The designer drugs enter the United States either through the mail or across the Mexican or Canadian border, he said, and often are sold at head shops and other retail stores.

State and federal lawmakers are reviewing legislation designed to improve response against new synthetic narcotics, Botticelli said, and the United States is leading discussions with international partners to improve the global response to these drugs.

But right now, law enforcement often is several steps behind the traffickers because U.S. laws aren't flexible enough to quickly outlaw emerging drug analogs, Rosenberg told Congress.

"I almost feel each time I sign an administrative control regulation that I'm simply telling the bad guys, 'Not this one any more. Move over here.' And that's what they do," Rosenberg said. "For every one substance we've controlled, legislatively or administratively, there are 11 more out there that are uncontrolled."

FDA Approves Rayaldee (calcifediol) to Treat Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

OPKO Health, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Rayaldee (calcifediol) extended release capsules for the treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Rayaldee is a patented extended release product containing 30 mcg of a prohormone called calcifediol (25-hydroxyvitamin D3).

 calcifediol

"FDA's approval of Rayaldee represents an important milestone for OPKO," noted Dr. Phillip Frost, CEO and Chairman of OPKO. "Rayaldee is the first product to receive FDA approval for this important indication and is one of OPKO's many pharmaceutical products being developed for significant medical problems which will benefit from new treatment options."

Results from two 26 week placebo controlled, double blind phase 3 trials demonstrated that a larger proportion of stage 3 or 4 CKD patients with SHPT and vitamin D insufficiency achieved ≥30% reductions in plasma intact parathyroid hormone (iPTH) when treated with Rayaldee than with placebo. Vitamin D insufficiency was corrected in more than 80% of the patients receiving Rayaldee compared with less than 7% of subjects receiving placebo. Mean serum calcium and phosphorus levels increased by 0.1 mg/dL during Rayaldee treatment compared to placebo treatment, but these changes were deemed clinically irrelevant. No differences in Rayaldee's efficacy or safety were observed between patients with stage 3 CKD or stage 4 CKD.

"Rayaldee fills a large void in the current treatment options for SHPT in predialysis patients," commented Dr. Charles W. Bishop, CEO of OPKO's Renal Division. "The current standard of care is high dose vitamin D supplementation, an approach for treating SHPT that is neither FDA approved nor demonstrated to be safe and effective in this population. SHPT is a progressive disease that becomes increasingly debilitating and difficult to treat, necessitating timely and effective treatment."

"Rayaldee is an important new option for treating SHPT in patients with stage 3 or 4 CKD and vitamin D insufficiency," stated Kevin J. Martin, Director of Research, Division of Nephrology at Saint Louis University School of Medicine. "The great majority of SHPT cases in this patient population are associated with vitamin D insufficiency, a problem that Rayaldee can correct."

About Rayaldee

Rayaldee (calcifediol) extended release capsules are approved by the U.S. Food and Drug Administration (FDA) for the treatment of SHPT in adult patients with stage 3 or 4 CKD and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Rayaldee has a patented formulation designed to raise serum total 25-hydroxyvitamin D (prohormone) concentrations to targeted levels (at least 30 ng/mL) and to reduce elevated iPTH. OPKO expects to launch Rayaldee in the U.S. through its dedicated renal sales force in the second half of 2016. Rayaldee is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis. The full prescribing information for Rayaldee will be available at www.opkorenal.com.

Potential side effects of Rayaldee include hypercalcemia (elevated serum calcium), which can also lead to digitalis toxicity, and adynamic bone disease with subsequent increased risk of fractures if intact PTH levels are suppressed by Rayaldee to abnormally low levels. Severe hypercalcemia may require emergency attention; symptoms of hypercalcemia may include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss. Digitalis toxicity can be potentiated by hypercalcemia of any cause. Excessive administration of Rayaldee can cause hypercalciuria, hypercalcemia, hyperphosphatemia, or oversuppression of intact PTH. Common symptoms of vitamin D overdosage may include constipation, decreased appetite, dehydration, fatigue, irritability, muscle weakness, or vomiting. Patients concomitantly taking cytochrome P450 inhibitors, thiazides, cholestyramine, phenobarbital or other anticonvulsants may require dose adjustments and more frequent monitoring.

The most common adverse reactions in clinical trials (≥3% and more frequent than placebo) were anemia, nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure and constipation.

Blueberries' health benefits better than many perceive

In continuation of my update on blueberries

Qu and her colleagues wanted to determine how much consumers know about blueberry health benefits and see if there's a knowledge gap with blueberry health benefits among demographic groups. Using their findings, they will identify promotional opportunities for Florida blueberries.

Researchers surveyed more than 2,000 people in 31 states -- mostly on the East Coast and in the Midwest -- to see what they know about the health benefits of blueberries. Most were aware of the benefits of blueberries in warding off cancer and lowering the risk of heart disease. The UF/IFAS study also found that low-income populations tend to know less about blueberry health benefits.

"People being more familiar with blueberries as deterrents for cancer and heart disease may be related to the high general awareness of these two diseases," Qu said. "The fact that cancer and heart diseases are the leading causes of death in America may have led to more personal research related to preventing the diseases, leading to the respondents being exposed to these findings more than other benefits."

To help promote blueberries' health benefits, Qu and her colleagues suggest holding events during blueberry season, such as tastings or u-picks to draw consumers to the crop while providing a vehicle for information about blueberry health benefits.

Blueberries' health benefits better than many perceive  

Darapladib drug can protect against vision loss in diabetic patients

Researchers at Queen's University Belfast and University College London have discovered that a drug, originally developed to treat cardiovascular disease, has the potential to reduce diabetes related blindness.

According to recent WHO global estimates, 422 million people have diabetes. One of the most common complications of this disease is vision loss.  Diabetic Macular Oedema occurs in approximately 7 per cent of patients with diabetes and is one of the most common causes of blindness in the Western World. In the UK, this sight-threatening complication of diabetic retinopathy is associated with estimated health and social care costs of £116 million. The socio-economic burden will only increase with prevalence of diabetes rising by more than 50 per cent by 2030.

Queen's and UCL researchers, in partnership with  GlaxoSmithKline, found that the drug Darapladib inhibits an enzyme which is increased in people with diabetes and causes blood vessel leakage in the eye which leads to swelling of the retina and severe vision loss.

Currently, the most common treatments for patients with Diabetic Macular Oedema is an injection of a drug directly into to the eye every 4-6 weeks.  This therapy is very expensive and not effective for about half of all patients with Diabetic Macular Oedema.

The discovery by the Queen's and UCL teams demonstrates that Darapladib in form of a tablet has potential to reduce the need for monthly injections and provide protection against vision loss in a much wider group of patients with diabetes.

Speaking about the breakthrough, Professor Alan Stitt, from the Centre for Experimental Medicine at Queen's University, said: "Diabetes-related blindness is caused by high blood sugar levels damaging the blood vessels in the retina.  We have found that an enzyme called Lp-PLA2 which metabolises fats in the blood contributes to blood vessel damage and leakiness in the retina. The drug Darapladib acts as inhibitor of Lp-PLA2, and was originally developed for cardiovascular disease. Based on our break-though we are now planning a clinical trial and if successful we could soon see an alternative, pain-free and cost effective treatment for diabetic related blindness."

Dr Patric Turowski from the UCL Institute of Ophthalmology said: "With our study we show that a blood lipid produced by Lp-PLA2 constitutes a novel trigger factor in diabetic macular oedema and that use of Darapladib may not only constitute an cost-effective alternative to current DMO treatments but has the potential to be effective for patients that currently do not respond to standard treatment."

Fixed-dose combination of sacubitril and valsartan for heart failure shows differing added benefit

In continuation of my update on Valsartan and Sacubitril

           Valsartan  Sacubitril 

The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function. In its early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) derived an indication of considerable added benefit versus the appropriate comparator therapy enalapril from the data: The positive effects regarding mortality, hospitalizations and quality of life largely outweighed the negative effect in non-severe side effects.

In the following commenting procedure, the drug manufacturer subsequently submitted sensitivity analyses and data, and a possible effect modification by the subgroup characteristic diabetes mellitus was pointed out. IQWiG investigated this in an addendum and concluded that there is an indication of a minor added benefit for diabetes patients. For patients without diabetes, in contrast, an indication of considerable added benefit of the drug combination remains.

Sensitivity analyses did not change assessment of the added benefit

The PARADIGM-HF study, on which the dossier was based, contained a so-called run-in phase to ensure that the participants tolerated the target dose of the study medication. About 20 per cent of the participants dropped out of the study in this phase. As noted by IQWiG in its dossier assessment, the rate of adverse events may be underestimated as a result, and more so under the drug combination than in the comparator arm.

To account for this, the manufacturer now presented sensitivity analyses. However, these analyses neither considered the outcomes of interest nor were methodologically adequate to remedy this deficiency. They did therefore not change the assessments from the dossier assessment.

Quality of life: indication of added benefit confirmed

Regarding health-related quality of life and health status, the manufacturer subsequently submitted analyses that increase the certainty of conclusions in comparison with the dossier assessment. For quality of life, there is now an indication of an added benefit both for clinically relevant improvement and for clinically relevant worsening. For health status, there is still no advantage of sacubitril/valsartan. Hence there is still no hint of an added benefit for this outcome.

Diagnosis of diabetes as relevant subgroup characteristic

There was proof of an effect modification in the outcome "mortality": Whereas there was an indication of an added benefit of sacubitril/valsartan in comparison with enalapril for patients without diabetes mellitus, there was no hint of an added benefit for patients with diabetes.

Overall, there were therefore still both positive effects and a negative effect. Due to the effect modification by the characteristic "diabetes", an indication of minor added benefit remains for patients with this disease, whereas there is still an indication of considerable added benefit for patients without diabetes.