Merck announced this week that it is suspending the availability of Tredaptive worldwide. The decision is in line with a recommendation from the European medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). The company has recommended that doctors stop prescribing Tredaptive and discontinue treatment with the drug for patients currently taking it. Merck is contacting regulatory agencies in countries where the drug is available, working with them to contact health care providers and pull Tredaptive.

“Patients currently taking Tredaptive are our priority, and we are committed to continue to work with regulatory agencies around the world to ensure that physicians have appropriate information as we take steps to suspend the availability of Tredaptive,” said Dr. Michael Rosenblatt, Chief Medical Officer at Merck.

Tredaptive is approved in around 70 countries, and is available in around 40 countries, including many in Europe. Its trade names include Pelzont, Trevaclyn, and Cordaptive. Merck sold $13 million worth of Tredaptive in the first three quarters of 2012.

Canagliflozin, which Johnson & Johnson has given the proposed trade name of Invokana, will, if further approved by the FDA later this year, be the first of a new type of diabetes drugs to be available in the U.S. It is a selective glucose co-transporter 2 inhibitor that blocks the reabsorption of glucose by the kidneys, which increases glucose excretion and lowers blood glucose levels. People with type 2 diabetes have kidneys that reabsorb greater-than-normal amounts of glucose back into the body.

“We are pleased with the positive recommendation from the committee and look forward to working with the FDA to bring this important new therapy to patients in the U.S. to help them manage their type 2 diabetes,” said Dr. Peter Stein, head of the Metabolism Development and Diabetes Disease Area departments at Janssen Research & Development, the Johnson & Johnson R&D company that developed the drug. “Today’s outcome represents an important step toward achieving that goal.”

The approval came after the results of a phase 3 clinical trial were presented at diabetes conferences last year. According to Janssen, the trial, which looked at 10,285 patients, was the “largest late-stage development program for an investigational pharmacologic product for the treatment of type 2 diabetes” ever submitted to health authorities. The results showed that canagliflozin improved glycemic control and was associated with weight loss and lower blood pressure. The side effects of the drug included yeast infections and urinary tract infections.

“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” said Dr. Morris Birnbaum, a researcher at the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania. “But we didn’t really know how the drug accomplished that.”

It was suggested in the past that metformin reduces glucose by activating an enzyme called AMPK. However, this hypothesis was shot down in 2010 when researchers found that mice without AMPK in their livers still responded to metformin, suggesting the drug works in a different way.

Birnbaum and his colleagues this week published the results of a new study in the journal Nature. Their research found that metformin antagonizes the action of glucagon, which reduces fasting glucose levels. Metformin was also shown to accumulate AMP in mice, which leads to the blocking of glucagon-dependent glucose output from the liver.

While the new discovery might be seen as an exercise in curiosity, the new study’s findings may lead to new drugs that work similarly to metformin. The study’s authors stated that new drugs could get around metformin’s affect on cell mitochondria, avoiding some of the side effects that go along with the drug.

(Image courtesy Morris Birnbaum, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania/Nature)

“Blood clots in the heart can cause a disabling stroke if the clots travel to the brain,” said Dr. Norman Stockbridge, director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “Anti-clotting drugs lower the risk of having a stroke by helping to prevent blood clots from forming.”

Eliquis was approved following a safety and efficacy clinical trial that compared the drug to another anti-clotting drug called warfarin. The trial, which looked at over 18,000 patients, found that patients on Eliquis had fewer strokes than those on warfarin.

The medication is not, however, for those who have heart valve problems. Likewise, patients with prosthetic heart valves are not recommended to take the new drug, as they were not part of the clinical trial. As with most anti-clotting drugs, bleeding uncontrollably is the biggest risk for those on Eliquis, as the FDA states there is no agent that can reverse the drug’s anti-coagulant effects.

“With a population that is living longer, the prevalence of nonvalvular atrial fibrillation is increasing, but many patients are still not being managed effectively with warfarin,” said Dr. Christopher Granger, lead investigator on the Eliquis trial and a professor of medicine at the Duke Clinical Research Institute. “Eliquis represents a significant advance over warfarin for health care professionals to reduce the risk of stroke in patients with nonvalvular atrial fibrillation.”

The trial, conducted at Oxford University and funded by Merck, looked at 25,673 patients at high risk for heart attack. The patients were given either Tredaptive or placed on standard stating therapy and followed for a median of 3.9 years.

Researchers found that the drug did not reduce the patients’ risk for heart attacks, strokes, necessary bypass surgeries, or death due to heart attack. Worse still, patients in the trial were found to have an increased risk for “serious,” though non-fatal, side effects.

“While we are disappointed in these results, we thank the investigators who have conducted the study and the patients who have participated in it,” said Peter Kim, president of Merck Research Laboratories. “We are committed to working closely with the independent research team at Oxford University and with regulatory agencies to understand the results and determine next steps.”

Tredaptive, also marketed as Cordaptive, Pelzont, and Trevaclyn, is already approved in around 70 countries, including some in Europe. It is already sold in around 40 countries, and saw $13 million in sales during the first three quarters of 2012. Merck is now sharing the results of the trial with regulators in the countries where the drug is approved.

The study, published in the journal The Lancet, looked at more than 10,000 U.S. veterans, both men and women, who had been diagnosed with a high cholesterol condition called dyslipidaemia. The participants were, on average, 60 years old. Over the course of 10 years, death rates were lowest for study participants who were both taking cholesterol-lowering medication (statins) and got regular exercise.

Study participants who were fit and taking statins lowered their risk of death over the 10-year period by 70%. Those who exercise but did not take statins lowered their risk of death by around 50%. The study participants who were least fit and did not take statins saw their risk of death rise by 35%. The study was controlled for the participants’ age, sex, ethnicity, weight, heart disease history, and the use of other drugs.

“The fitness necessary to attain protection that is much the same or greater than that achieved by statin treatment in unfit individuals is moderate and feasible for many middle-aged and older adults through moderate intensity physical activity such as walking, gardening, and gym classes,” said Dr. Peter Kokkinos, lead author of the study and a researcher at the Veterans Affairs Medical Centre. “Treatment with statins is important, but better fitness improves survival significantly and is a valuable additional treatment or an alternative when statins cannot be taken,”

“Many of the drugs that interact with grapefruit are highly prescribed and are essential for the treatment of important or common medical conditions,” said Dr. David Bailey, lead author of the study. “Recently, however, a disturbing trend has been seen. Between 2008 and 2012, the number of medications with the potential to interact with grapefruit and cause serious adverse effects…has increased from 17 to 43, representing an average rate of increase exceeding 6 drugs per year. This increase is a result of the introduction of new chemical entities and formulations.”

Many of the drugs that interact with grapefruit are also commonly abused, including benzodiazepines, oxycodone, and erectile dysfunction drugs. The side effects of drug interactions with grapefruit can include acute kidney failure, respiratory failure, gastointestinal bleeding, bone marrow suppression in people with compromised immune systems, renal toxicity, and sudden death.

Grapefruit, seville oranges, limes, and pomelos contain organic compounds called furanocoumarins, which inhibits the CYP3A4 enzyme. CYP3A4 normally metabolizes drugs, inactivating the effects of around 50% of all medication. For drugs in which very little of the actual drug is absorbed in to the bloodstream, the effect is essentially a mega-dose of the medication, which can lead to overdose. Interactions can occur even hours after grapefruit is consumed.

“Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient’s diet, it is very unlikely that they will investigate it,” said the study’s authors. “In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general healthcare community.”

According to the review, people over 45 years old are the prime purchasers of grapefruit, and also the people who receive the most prescriptions for drugs. As a result, older people are most vulnerable to adverse grapefruit interactions.

“The current trend of increasing numbers of newly marketed grapefruit-affected drugs possessing substantial adverse clinical effects necessitates an understanding of this interaction and the application of this knowledge for the safe and effective use of drugs in general practice,” said the study’s authors.

In the study, published this week in the Journal of Neuroscience, the drug rosiglitazone was used on mice that have been genetically engineered to serve as models for Alzheimer’s disease. Researchers found that treatment with the drug improved learning and memory in the mice, while it also normalized insulin resistance.

The researchers believe that the drug reduced the negative influence of Alzheimer’s on a brain-signaling molecule called extracellular signal-regulated kinase (ERK). ERK becomes hyperactive in the brains of Alsheimer’s patients when they begin to exhibit mild cognitive impairment. This leads to improper synaptic transmission between neurons. The study shows that the drug activates the peroxisome proliferator-activated receptor gamma (PPARy) pathway in the brain, reducing ERK activity.

“Using this drug appears to restore the neuronal signaling required for proper cognitive function,” said Larry Denner, lead author of the study and a University of Texas Medical Branch (UTMB) professor. “It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer’s patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer’s.”

The new research was a joint UTMB effort by animal cognitive neuroscientists, biochemists, molecular biologists, mass spectrometrists, statisticians, and bioinformaticists.

“We were extraordinarily lucky to have this diverse group of experts right here on our campus at UTMB that could coalesce to bring such different ways of thinking to bear on a common problem,” said Denner. “It was quite a challenge to get all of these experts communicating in a common scientific language. But now that we have this team working, we can move on to even more detailed and difficult questions.”

Omalizumab currently has a U.K. marketing authorization as an add-on therapy for persistent allergic asthma in adults and children. It works by blocking immunoglobulin E antibodies from attaching to allergens.

NICE stated that new evidence, including new mortality data, that has be come available influenced its decision. It also took into account the dosing schedule for the drug, and the effect that had on its cost effectiveness. These factors and other “uncertainties in the evidence and analysis presented,” influenced NICE to withhold a recommendation for omalizumab. The health-related quality of life benefits of the drug are not currently considered quantifiable, and were not part of the economic modeling used by NICE.

“The Committee is aware that severe, persistent allergic asthma can have a detrimental effect on a person’s life and that omalizumab is an effective therapy for children, adolescents and adults with severe persistent allergic asthma,” said Sir Andrew Dillon, chief executive of NICE. “But new evidence that has become available since our original appraisal of omalizumab in 2007 indicates that it is not as clinically or cost-effective as was first thought. The Committee explored ways to identify a subgroup of people for whom omalizumab might provide a cost effective treatment, including using favorable assumptions in the modeling. In addition, the Committee recognized that there could be additional health-related benefits for patients and carers as a result of using omalizumab. However, there was no quantifiable data relating to these benefits. Unfortunately, the Committee was unable to continue to recommend omalizumab for use in the NHS. The next step is for the manufacturer and other consultees to respond to the Committee’s concerns.”

The twice-daily pill works by blocking molecules known as “Janus kinases.” The approval was based on the medication’s approval was based on its demonstrated effectiveness and safety in seven clinical trials. In all of the trials, adults with moderate to severe RA “experienced improvement in clinical response and physical functioning” when treated with Xeljanz. The drug was, however, associated with an increased increases in cholesterol and an increased risk of serious infections, including tuberculosis, cancers, and lymphoma.

“RA is a serious and disabling disease that affects people in their everyday lives, and many patients do not adequately respond or are intolerant to currently available therapies,” said Dr. Stanley Cohen, study investigator and clinical professor of rheumatology at the University of Texas Southwestern Medical School. “In clinical trials, Xeljanz significantly reduced the signs and symptoms of RA and improved physical function. As a physician, I am pleased that we have another choice for patients living with inadequately controlled, moderately to severely active RA.”

According to the FDA, RA is an autoimmune disease in which the body’s immune system attacks healthy tissue, leading to the inflammation of joints. The U.S. Centers for Disease Control and Prevention (CDC) estimates that it affects 1.5 million Americans.

Xeljanz was developed by Pfizer, and the company has agreed to conduct post-marketing clinical trials to evaluate the long-term safety of the drug.