GlyNAC supplementation reverses aging hallmarks in aging humans

We're Treating Low Back Pain All Wrong

In December 2019, I attended a National Academies of Sciences workshop on the role of non-pharmacological approaches to pain management. At the end of the meeting, as expected, panelists concluded that more research was needed. However, to my surprise, several scientists also called for immediate action on the approach to treating low back pain. They called for clinicians to implement the evidence we already have into clinical practice; for policymakers to enact payment reform that would support such implementation; for all of us to commit to making the cultural changes needed to ensure that patients have access to the right care from the right provider at the right time.

Where did this response come from? It stemmed from the fact that low back pain has been over-medicalized, making a very bad problem worse, and the need for realigned incentives that encourage clinicians to follow current evidence and treatment recommendations.

No health condition leads to greater disability or higher costs than low back pain, and commonly used medical treatment approaches often lead to more harm than benefit. Imaging is rarely necessary to develop an evidence-based treatment plan and can exacerbate pain catastrophizing, as well as lead to incidental findings "rabbit holes." Prescription medications may be helpful to some patients in certain circumstances, but overall the risks often outweigh the benefits. According to the CDC, more than 260,000 deaths in America from 1999 to 2020 involved prescription opioids. Non-steroidal anti-inflammatory drugs (NSAIDs) can cause intestinal bleeding, especially in older adults, and are associated with a higher incidence of myocardial infarction. Surgery and corticosteroids can lead to short-term pain relief for some patients but results are often not sustained nor superior to less invasive options.

Most importantly, many of these medical diagnostic and treatment approaches -- early imaging, surgical consults, corticosteroid injections, prescription opioids and NSAIDs -- may actually increase the number of patients who transition from acute to chronic pain.

The problem is not the lack of evidence. The CDC, the Veterans Health Administration, and the American College of Physicians (ACP) have released comprehensive guidelines backed by highly convergent supportive evidence for the management of low back pain. Recommended first line treatments include non-pharmacological approaches such as exercise, education, self-care options, spinal manipulation, acupuncture, and massage. The ACP guideline in particular calls for patients and clinicians to consider the use of non-pharmacological treatment approaches for low back pain before trying prescription medications.

The problem is that we are not following the evidence. There are multiple barriers to widespread implementation of known best practices. Health systems are slow to change, especially when such change may not be in their financial best interests. Orthopedic surgeons are consistently rated among the top health system income generators, bringing in an average of $3.3 million per year. Primary care physicians may not have learned about non-pharmacological treatments in medical school and are often working with frightened patients who understandably want a clear explanation for their pain and a quick fix -- a pill, an injection, even surgery.

Additionally, there is a sharp disconnect between existing payment policy and best practices for low back pain. Payors provide robust reimbursement for prescription medications, corticosteroid injections, and surgery. In contrast, private and public insurers often place significant limitations on coverage for guideline concordant treatments such as chiropractic care, acupuncture, and massage. Such policies offer little incentive for clinicians and health systems to change.

If we want real change, it will take an entire team of "committed citizens."

Health systems can ensure they are staffed with providers whose clinical practices are better aligned with guideline recommendations. Payors can change their policies to align payment with guideline recommendations. Some health systems and insurance companies are moving in the right direction. Duke University Health System has instituted the Spine Health Program to offer coordinated, guideline-concordant care to patients with low back pain. United Healthcare does not charge co-pays for members who see a chiropractor or physical therapist first for low back pain. Traditional Medicare recently began offering limited coverage for acupuncture.

We also need to promote clinician education on the evidence regarding proper diagnosis and treatment of low back pain. We can become familiar with the ACP Guideline and read the excellent Lancet series on low back pain. We can tell our patients that MRIs can lead to worse outcomes, surgery is rarely necessary, and let them know that the ACP recommends the use of non-pharmacological treatments before prescription medications. Most importantly, we can, in the absence of red flags, refrain from ordering those tests or treatments unless they are clearly needed after the patient engages in a full course of evidence-based non-pharmacological treatment.

I can't ignore the fact that part of the issue is systemic: the U.S. Healthcare system is built upon the belief that patients benefit from seeking care. But that is often not the case for low back pain. By ignoring the evidence, over-medicalizing this condition, and continuing to tolerate policies that incentivize the wrong treatments, we are causing real harm to those who trust us to care for them.

Christine Goertz, DC, PhD, is a professor in musculoskeletal research at the Duke Clinical Research Institute n Durham, North Carolina, vice chair for Implementation of Spine Health Innovations in the Department of Orthopaedic Surgery at Duke University, and core faculty at the Duke Margolis Center for Health Policy.

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The Drug Company That Prospered Without Creating Any Drugs

The new drug looked so promising — except for that one warning sign.

At the American College of Rheumatology's annual meeting in 2008, Duke University's Dr. John Sundy proudly announced that pegloticase, a drug he'd helped develop, was astoundingly effective at treating severe gout, which affects perhaps 50,000 Americans. In about half of those who had taken it, the drug melted away the crystalline uric acid deposits that encrusted their joints to cause years of pain, immobility, or disfigurement.

But Sundy also disclosed an unsettling detail: In one clinical trial, patients who got the drug were more likely to develop heart problems than those who didn't. The day after Sundy's talk, the stock price of Savient Pharmaceuticals, which developed the drug with Duke scientists, plunged 75%.

That danger signal would disappear in later studies, and the FDA approved pegloticase, under the trade name Krystexxa, two years later. But the small biotech company never recovered. In 2013, Savient was sold at auction to Crealta, a private equity venture created for the purpose, for $120 million.

Two years later, a young company now called Horizon Therapeutics bought Crealta and its drug portfolio for $510 million.

Even at that price, it proved a good deal. Krystexxa brought in $716 million in 2022 and was expected to earn $1 billion annually in coming years.

Although Horizon says it now has 20 drugs under development, in its 15 years of existence it has yet to license a product it invented. Yet the company has managed to assemble a war chest of lucrative drugs, in the process writing a playbook for how to build a modern pharmaceutical colossus.

As the White House and both parties in Congress grapple with reining in prescription drug prices, Horizon's approach reveals just how difficult this may be.

Horizon's strategy has paid off handsomely. Krystexxa was just one of the many shiny objects that attracted Amgen, a pharmaceutical giant. Amgen announced in December that it intends to buy Horizon for $27.8 billion, in the biggest pharmaceutical industry deal announced in 2022.

Horizon's CEO, Tim Walbert, who will reportedly get around $135 million when the deal closes, has mastered a particular kind of industry expertise: taking drugs invented and tested by other people, wrapping them expertly in hard-nosed marketing and warm-hued patient relations, raising their prices, and enjoying astounding revenues.

He's done this with unusual finesse — courting patients with concierge-like attention and engaging specialist clinicians with lunches, conferences, and research projects, all while touting his own experience as a patient with a rare inflammatory disease. Walbert's company has been particularly adept at ensuring that insurers, rather than patients, bear the costly burdens of his drugs.

A federal prosecutor in 2015 began examining allegations that Horizon's patient assistance program had worked with specialty pharmacies to evade insurers' efforts to shun Horizon's expensive drugs. A separate probe opened in 2019 over alleged kickbacks to pharmacy benefit managers, companies that negotiate to get Horizon's drugs covered by insurers. Those investigations appear to be no longer active, Horizon spokesperson Catherine Riedel said. The company this year disclosed a third probe, concerning methods the company allegedly used to get prior authorization of its drugs. Justice officials did not respond to requests for comment on the investigations.

An injection of marketing

To help sell its drugs, Horizon blankets specialist physicians with marketing and peer-to-peer appeals. Its payments to physicians for things like consulting, speeches, and meals totaled $8.7 million in 2021, compared with the $10 million it paid them for research, federal records show. By contrast, Seagen, a biotech company of roughly the same size, paid doctors a total of $116 million, with nearly $112 million of that pegged for research. Riedel said Horizon's marketing and educational approaches were "necessarily unique" because of the challenges of treating rare and neglected diseases.

Walbert launched Horizon in 2008 in the Chicago area by combining and refashioning generic drugs into single pills. Duexis, Horizon's first drug, is a mixture of generic Motrin and Pepcid. Its Vimovo combines generic Aleve and Nexium. In a 2017 article, a ProPublica reporter described being prescribed Vimovo for a shoulder injury. It cost him nothing, but his insurer was billed $3,252 for pills that together cost about $40 for a month's supply in generic form. Horizon sold more than $57 million worth of Vimovo that year.

In 2014 and 2015, respectively, Horizon picked up two relatively new drugs that had no generic versions: the immunosuppressant Actimmune and Ravicti, which treats a rare genetic disorder. Soon Horizon was charging more than $50,000 a month for each, placing Actimmmune fourth and Ravicti second on GoodRx's 2020 list of the most expensive U.S. Drugs.

Horizon's net sales soared from $20 million in 2012 to $981 million in 2016; Walbert's pay package followed suit, topping an astronomical $93.4 million in 2015 in salary and stock. Stock analysts questioned the long-term soundness of a strategy of simply selling old drugs for mind-boggling prices, but Walbert was using the cash to refashion the company as a rare-diseases franchise.

His approach would make Walbert a darling of pharmaceutical investors and his board, which lavished him with over $20 million in compensation each of the past three years. While most biotechs and startups borrow heavily from venture capital to do science and have no idea how to develop and market a drug, Walbert got cash coming in quickly. "He did it backwards," said Annabel Samimy, an analyst at Stifel Financial Corp. "Horizon built commercial platforms before they got into drug development."

Generating "robust sales of what sounded like not very interesting drugs" allowed Walbert "to start a company on not very much," said Oppenheimer analyst Leland Gershell. All the while, Horizon funded and cultivated the patient advocacy groups that can help lobby for a drug to be approved by the FDA and placed on insurers' formularies, the lists of drugs health plans cover for patients.

Capitalizing on his own illness?

As Walbert and his spokespeople often point out, Walbert and his youngest son suffer from a rare disease, and Walbert also has an autoimmune disease. Walbert won't name the diseases, but has said he's taken the anti-inflammatory injectable Humira since 2003 — the year he led that drug's commercial launch as a vice president at Abbott Laboratories. Humira has become the bestselling drug in history, with about $200 billion in all-time global sales.

In 2014, Walbert moved Horizon's headquarters to Ireland, which nearly halved its tax rate. A year later it gained control of Krystexxa, and in 2017 it bought, for $145 million, a failing company that produced Tepezza, a drug for thyroid eye disease, which causes unsightly eye bulging and pain.

Tepezza quickly became a blockbuster, with $3.6 billion in total sales in 2021 and 2022. The company conducted additional clinical research on both Tepezza and Krystexxa, but it also spent heavily promoting these and other drugs to specialists who could prescribe them.

All the while it steadily raised prices. Savient put Krystexxa on the market in 2011 at $2,300 per injection. Horizon charges roughly 10 times as much. Six months of Tepezza treatment can run more than $400,000.

Horizon's publicity emphasized the company's sensitivity to patients, and its constant contact with disease advocates.

"Our scientists are attuned to the unmet needs of patients, their diagnostic and therapeutic journey," Bill Rees, Horizon's vice president for translational sciences, told KFF Health News. "It's the marrying of the basic clinical science with a focus on the needs of the patient that differentiates us."

To make sure patients keep using its drugs, clinicians say, Horizon staffers negotiate with insurance carriers, and the company offers drug discounts to lower-income patients while swaddling them with attention from its medical staff.

"Horizon has a nurse talk to each and every patient before every appointment," said Dr. Brigid Freyne, who treats around half a dozen patients each year with Krystexxa at her Murrieta, California, rheumatology clinic. "The patients who come in here are highly motivated to get their IV. They get the message that it's very important and they are fortunate to get the medicine."

None of the manufacturers of her other infusion drugs shower patients with this kind of attention, she said.

While at Abbott, Walbert pioneered direct-to-consumer advertising for specialty drugs like Humira, a trend that aggravated insurers, who anticipated, correctly, that they would soon be shelling out billions for expensive drugs.

Horizon's marketing plan for Krystexxa includes direct-to-consumer ads aimed at driving patients to specialists. The drug is designed for recalcitrant gout patients, who often have large lumps on their fingers, feet, and kidneys. Many, though not all, are heavy drinkers of beer or soda sweetened with high-fructose corn syrup, which can increase the buildup of uric acid, the cause of gout, said Dr. Robert McLean of Yale University.

While Krystexxa can help patients with advanced gout, the American College of Rheumatology views it as a drug of last resort, with plenty of cheaper, early intervention alternatives available.

"I prescribe it maybe once a year," McLean said. "From a cost-effectiveness standpoint, it warrants questioning."

Horizon recently started a publicity campaign addressed to all gout sufferers, urging them to see a rheumatologist or a nephrologist — the specialists it has targeted with Krystexxa educational materials — before the disease does too much harm.

"Horizon would like you to say, 'Everyone with serious gout should be started on Krystexxa,'" said Dr. James O'Dell, a rheumatologist at the University of Nebraska Medical Center. The Horizon pitchmen he deals with are "nice guys, but we don't believe that's the best way."

The company defends its marketing practices. "We learn what matters most to patient communities and act. This approach has been validated by independent third-party research," said Riedel.

The Federal Trade Commission said in January it was seeking more information on the Amgen-Horizon merger. Sen. Elizabeth Warren (D-Mass.), citing high prices for Horizon and Amgen drugs, urged the agency to nix the deal.

This article was reprinted from khn.Org with permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonpartisan health care policy research organization unaffiliated with Kaiser Permanente.

REPRIEVE Stopped: Big MACE Reductions With Statins In HIV+ Subjects

A daily statin can reduce the risk of new-onset cardiovascular disease in people living with HIV, according to preliminary results from the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial. Top-line results for this large, National Institutes of Health-funded study were released yesterday following an interim analysis indicating that subjects randomized to pitavastatin had a 35% lower risk of major adverse cardiovascular events compared with those receiving a placebo. 

Speaking with TCTMD, co-principal investigator Steven K. Grinspoon, MD (Harvard Medical School, Boston, MA), clarified that the reduction in MACE occurred within a mean follow-up of 5 years and was "even beyond what we expected—a very robust signal."

Right now, use of statins in HIV-positive patients with no cardiovascular risk factors would typically only happen at physician discretion.

As co-principal investigator Pamela Douglas, MD (Duke Clinical Research Institute, Durham, NC), pointed out to TCTMD, for now HIV is considered merely a "risk modifier" in the current primary prevention guidelines. "REPRIEVE basically says that the usual considerations of LDL and risk score are less relevant in this population," she said in an email.

Younger Patients, No Other Risk Factors

Many HIV patients are younger than the typical patient population seeing a cardiologist or prescribed statins today. "What [REPRIEVE] does is it expands our knowledge to suggest that patients 40 to 75 who have moderate-to-low risk, who have HIV and a normal LDL will benefit from statin therapy," Grinspoon said. "I hope guidelines will be expanded to include this."

Launched in 2015, REPRIEVE randomized 7,769 HIV-positive subjects at low or moderate risk of developing cardiovascular disease to pitavastatin or placebo; more than 30% of the cohort are women. Subjects enrolled at one of 120 sites in 12 countries across North and South America, Asia, Africa, and Europe are being followed for up to 8 years.

It is the first, large-scale clinical study to test a primary CVD prevention strategy in people living with HIV and, according to Grinspoon, represents a major new treatment for these patients.

"Although the life span gap has been closing, there is still a gap—patients with HIV still don't live quite as long as non-HIV patients. And although this is getting a little better, the comorbidity gap has not been really closing, and one of the most common comorbidities is cardiovascular disease," he explained.

Rates of CVD in HIV-positive patients are roughly twice that seen in the general population. "For years, the main thing was that we needed to get the virus under control, and studies like SMART showed us that treatment with antiretroviral therapy [ART], with good control of the virus, actually did lead to a reduction in comorbidities as well as viral infections."

Over time, Grinspoon said, "I think the story has evolved from thinking we need to get everyone on ART and fully suppress the virus as much as possible, to now thinking that this may not be sufficient and there appears to be an added benefit of using a statin medicine on top of ART to further reduce ongoing comorbidities, which are very common in this group, including cardiovascular disease."

He continued: "What we tested was adding on a statin to people who are on antiretroviral therapy: those people were having heart attacks and strokes, and we reduced those. . . . In that group we could further add to the effects of antiretroviral therapy to further decrease inflammation and improve traditional risk factors at the same time."

Of note, he added, rates of statin side effects were similar in REPRIEVE to those seen in the general population.

According to Grinspoon, investigators hope to get their data presented and published as soon as possible.

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