Tag: observational studies

Being Alive Is Bad for Your Health

In 2016, I gave up Diet Coke. This was no small adjustment. I was born and raised in suburban Atlanta, home to the Coca-Cola Company’s global headquarters, and I had never lived in a home without Diet Coke stocked in the refrigerator at all times. Every morning in high school, I’d slam one with breakfast, and then I’d make sure to shove some quarters (a simpler time) in my back pocket to use in the school’s vending machines. When I moved into my freshman college dorm, the first thing I did was stock my mini fridge with cans. A few years later, my then-boyfriend swathed two 12-packs in wrapping paper and put them under his Christmas tree. It was a joke, but it wasn’t.

You’d think quitting would have been agonizing. To my surprise, it was easy. For years, I’d heard anecdotes about people who forsook diet drinks and felt their health improve seemingly overnight—better sleep, better skin, better energy. I’d also heard whispers about the larger suspected d angers of fake sweeteners. Yet I’d loved my DCs too much to be swayed. Then I tried my first can of unsweetened seltzer at a friend’s apartment. After years of turning my nose up at the thought of LaCroix, I realized that much of what I enjoyed about Diet Coke was its frigidity and fizz. That was enough. I switched to seltzer on the spot, prepared to join the smug converted and receive whatever health benefits were sure to accrue to me for my good behavior.

Except they never came. Seven years later, I feel no better than I ever did drinking four or five cans of the stuff a day. I still stick to seltzer anyway—because, you know, who knows?—and I’ve mostly forgotten that Diet Coke exists. But the diet sodas had not, as it turns out, been preventing me from getting great sleep or calming my rosacea or feeling, I don’t know, zesty. Besides the caffeine, they appeared to make no difference in how good or bad I felt at all.

Yesterday, Reuters reported that the WHO’s International Agency for Research on Cancer will soon declare aspartame, the sweetener used in Diet Coke and many other no-calorie sodas, as “possibly carcinogenic to humans.” I probably should have felt vindicated. I may not feel better now, but many years down the road (knock on wood), I’ll be better off. I’d bet on the right horse! Instead, I felt nothing so much as irritation. Over the past few decades, a growing number of foods and behaviors have become the regular subject of vague, ever-changing health warnings—fake sweeteners, real sugar, wine, butter, milk (dairy and non), carbohydrates, coffee, fat, chocolate, eggs, meat, veganism, vegetarianism, weightlifting, drinking a lot of water, and scores of others. The more warnings there are, the less actionable any particular one of them feels. What, exactly, is anyone supposed to do with any of this information, except feel bad about the things they enjoy?

It’s worth reviewing what is actually known or suspected about diet sodas and health. The lion’s share of research on this topic happens in what are known as observational studies—scientists track consumption and record health outcomes, looking for commonalities and trends linking behavior and effects. These studies can’t tell you if the behavior caused the outcome, but they can establish an association that’s worth investigating further. Regular, sustained diet-soda consumption has been linked to weight gain, Type 2 diabetes, and increased risk of stroke, among other things—understandably troublesome correlations for people worried about their health. But there’s a huge complicating factor in understanding what that means: For decades, advertisements recommended that people who were already worried about—or already had—some of those same health concerns substitute diet drinks for those with real sugar, and many such people still make those substitutions in order to adhere to low-carb diets or even out their blood sugar. As a result, little evidence suggests that diet soda is solely responsible for any of those issues—health is a highly complicated, multifactorial phenomenon in almost every aspect—but many experts still recommend limiting your consumption of diet soda as a reasonable precaution.

A representative for the IARC would neither confirm nor deny the nature of the WHO’s pending announcement on aspartame, which will be released on July 14. For the sake of argument, let’s assume that Reuters’s reporting is correct: In two weeks, the organization will update the sweetener’s designation to indicate that it’s “possibly carcinogenic.” To regular people, those words—especially in the context of a health organization’s public bulletins—would seem to imply significant suspicion of real danger. The evidence may not yet all be in place, but surely there’s enough reason to believe that the threat is real, that there’s cause to spook the general public.

Except, as my colleague Ed Yong wrote in 2015, when the IARC made a similar announcement about the carcinogenic potential of meat, that’s not what the classification means at all. The IARC chops risk up into four categories: carcinogenic (Group 1), probably carcinogenic (Group 2A), possibly carcinogenic (Group 2B), and unclassified (Group 3). Those categories do one very specific thing: They describe how definitive the agency believes the evidence is for any level of increased risk, even a very tiny one. The category in which aspartame may soon find itself, 2B, makes no grand claims about carcinogenicity. “In practice, 2B becomes a giant dumping ground for all the risk factors that IARC has considered, and could neither confirm nor fully discount as carcinogens. Which is to say: most things,” Yong wrote. “It’s a bloated category, essentially one big epidemiological shruggie.”

The categories are not at all intended to communicate the degree of the risk involved—just how sure or unsure the organization is that there’s a risk associated with a thing or substance at all. And association can mean a lot of things. Hypothetically, regular consumption of food that may quadruple your risk of a highly deadly cancer would fall in the same category as something that may increase your risk of a cancer with a 95 percent survival rate by just a few percentage points, as long as the IARC felt similarly confident in the evidence for both of those effects.

These designations about carcinogenicity are just one example of how health information can arrive to the general public in ways that are functionally useless, even if well intentioned. Earlier this year, the WHO advised against all use of artificial sweeteners. At first, that might sound dire. But the actual substance of the warning was about the limited evidence that those sweeteners aid in weight loss, not any new evidence about their unique ability to harm your health in some way. (The warning did nod to the links between long-term use of artificial sweeteners and increased risks of cardiovascular disease, Type 2 diabetes, and premature death, but as the WHO noted at the time, these are understood as murky correlations, not part of an alarming breakthrough discovery.)

The same release quotes the WHO’s director for nutrition and food safety advising that, for long-term weight control, people need to find ways beyond artificial sweeteners to reduce their consumption of real sugar—in essence, it’s not a health alert about any particular chemical, but about dessert as a concept. How much of any sweetener would you need to cut out of your diet in order to limit any risks it may pose? The release, on its own, doesn’t specify. Consider a birthday crudités platter instead of a cake, just to be sure. (Is that celery non-GMO? Organic? Just checking.)

The media, surely, deserve our fair share of blame for how quickly and how far these oversimplified ideas spread. Many people are very worried about the food they eat—perhaps because they have received so many conflicting indicators over the years about how that food affects their bodies—and flock to news that something has been deemed beneficial or dangerous. At best, the research that many such stories cite is rarely definitive, and at worst, it’s so poorly designed or otherwise flawed that it’s flatly incapable of producing useful information.

Taken in aggregate, this morass of poor communication and confusing information has the very real potential to exhaust people’s ability to identify and respond to actual risk, or to confuse them into nihilism. The solution-free finger-wagging, so often about the exact things that many people experience as the little joys in everyday life, doesn’t help. When everything is an ambiguously urgent health risk, it very quickly begins to feel like nothing is. I still drink a few Diet Cokes a year, and I maintain that there’s no better beverage to pair with pizza. We’re all going to die someday.

Amanda Mull

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June 30, 2023
America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

Statins, one of the most extensively studied drugs on the planet, taken by tens of millions of Americans alone, have long had a perplexing side effect. Many patients—some 5 percent in clinical trials, and up to 30 percent in observational studies—experience sore and achy muscles, especially in the upper arms and legs. A much smaller proportion, less than 1 percent, develop muscle weakness or myopathy severe enough that they find it hard to “climb stairs, get up from a sofa, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. He’s had patients fall on the street because they couldn’t lift their leg over a curb.

But why should an anticholesterol drug weaken muscles in the arms and legs? Recently, two groups of scientists stumbled upon an answer. They didn’t set out to study statins. They weren’t studying cholesterol at all. They were hunting for genes behind a rare disease called limb girdle muscle dystrophy, in which muscles of the upper arms and legs—sound familiar?—become weak and waste away. After both teams tracked the disease through a handful of families in the U.S. and a Bedouin family in Israel, their suspicions separately landed on mutations in a gene encoding a particularly intriguing enzyme.

The enzyme is known as HMG-CoA reductase, and to doctors, it is not obscure. It is, in fact, the very enzyme that statins block in the process of halting cholesterol production. And so, the answers to two mysteries suddenly became clear at once: Dysfunction in this enzyme causes muscle weakness from both limb girdle muscular dystrophy and statins.

This connection between a rare disease and a common drug stunned the researchers. “It seemed too good to be true,” says Joel Morales-Rosado, a pathologist who worked on one of the studies as a postdoctoral researcher at the Mayo Clinic. “One of the first things you learn in medical school is association between statins and myopathy.” Now the answer as to why— along with a potential treatment for it—has emerged from the DNA of just a few patients living with a seemingly unrelated genetic disease.

The first patient the Mayo team studied had been showing signs of limb girdle muscular dystrophy since he was a child, and his symptoms worsened over time until he lost the ability to walk or breathe with ease. (The disease can also affect large muscles in the torso.) Now in his 30s, he wanted to know the genetic cause of his disease before having children and potentially passing it on to them. His two brothers had the disease as well. So the team looked for genes in which all three brothers had mutations in both copies, which is how they zeroed in on the gene for HMG-CoA reductase.

Six more patients from four other families confirmed the link. They too all had mutations in the same gene, and they too were all diagnosed with some degree of limb girdle muscular dystrophy. (Interestingly, for reasons we don’t entirely understand, they all have normal or low cholesterol.)

Unbeknownst to the Mayo team, a group of researchers halfway around the world was already studying a large Bedouin family with a history of limb girdle muscular dystrophy. This family also carried mutations in the gene encoding HMG-CoA reductase. Those afflicted began experiencing minor symptoms in their 30s, such as muscle cramps, that worsened over time. The oldest family members, in their late 40s or 50s, had lost all movement in their arms and legs. One bedridden woman had to be ventilated full-time through a hole in her windpipe. Another had died in their mid-50s, Ohad Birk, a geneticist and doctor at Ben-Gurion University of the Negev, in Israel, told me. When his team saw that this family had the mutations in HMG-CoA reductase, they too immediately recognized the potential link to statins.

This pair of studies in the U.S. and Israel “really strongly suggests” that statins cause muscle damage via the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in either study. The enzyme’s role had been suspected, he told me, but “it had never been proven, especially in humans.” (Questions still remain, however. The enzyme, for example, is found in tissues throughout the body, so why do these common side effects show up in muscles specifically?) Rosenson, at Mount Sinai, wondered if variations in this gene could explain why statins don’t affect everyone the same. Perhaps patients who suffer particularly severe muscle side effects already have less functional versions of the enzyme, which becomes problematic only when they start taking statins, which reduce its function even further. This research might end up concretely improving the life of at least some of the patients most severely affected by statins.

That’s because Birk’s team in Israel did not stop at simply identifying the mutation. For two decades, he and his colleagues have been studying genetic disorders in this Bedouin community in the Negev and developing genetic tests so parents can avoid passing them on to their children. (Cousin marriages are traditional there, and when two parents are related, they are more likely to carry and pass on the same mutation to a child.) With limb girdle muscular dystrophy, his team went one step further than usual: They found a drug to treat it.

This drug, called mevalonolactone, allows muscle cells to function more normally even without the HMG-CoA reductase enzyme. Birk’s team first tested it in mice given doses of statins high enough to weaken their limbs; those also given mevalonolactone continued to crawl and even hang upside down on a wire just fine. They seemed to suffer no ill effects. When that experimental drug was given to the Bedouin woman bedridden with limb girdle muscular dystrophy, she also started regaining control of her arms and legs. She could eventually lift her arm, sit up by herself, raise her knees, and even feed her grandchild on her own. It was a dramatic improvement. Birk told me he has since heard about dozens of patients with limb girdle muscular dystrophy around the world who may benefit from this experimental drug.

Mammen and others think the drug could help a small subset of patients who take statins as well. However, the majority of patients—those with relatively minor pains or weaknesses that go away after they switch statins or have their dosage reduced—probably don’t need this new treatment. It probably even undermines the whole point of taking statins: Mevalonolactone eventually gets turned into cholesterol in the body, so “you’re basically supplying the building blocks for making more cholesterol,” Mammen said. But for some people, numbering in the thousands, severe muscle weakness does not go away even after they stop taking statins. These patients have developed antibodies to HMG-CoA reductase, which Mammen suspects continue to bind and disable the enzyme.

Mammen is eager for these patients to try mevalonolactone, and he’s been in touch with Birk, who unfortunately doesn’t have enough of the drug to share. In fact, he doesn’t even have enough to treat all of the other family members in Israel who are clamoring for it. “We’re not a factory. We’re a research lab,” Birk told me. Mevalonolactone is available as a research chemical, but that’s not pure and safe enough for human consumption. Birk’s graduate student Yuval Yogev had to manufacture the drug himself by genetically engineering bacteria to make mevalonolactone, which he then painstakingly purified. Making a drug to this standard is a huge amount of work, even for commercial labs. Birk is looking for a pharmaceutical company that could manufacture the drug at scale—for both patients with limb girdle muscular dystrophy and those with the most severe forms of statin-associated muscle damage.

Back in 1980, the very first person to receive an experimental dose of statins suffered muscle weakness so severe, she could not walk. (She had been given an extremely high dose.) Forty years later, muscle pain and weakness are still common reasons patients quit these very effective drugs. This recent breakthrough is finally pointing researchers toward a better understanding of statins’ toll on muscles, even if they still can’t fix it for everyone.

Sarah Zhang

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June 27, 2023
Somehow, the Science on Masks Still Isn’t Settled

For many Americans, wearing a mask has become a relic. But fighting about masks, it seems, has not.

Masking has widely been seen as one of the best COVID precautions that people can take. Still, it has sparked ceaseless arguments: over mandates, what types of masks we should wear, and even how to wear them. A new review and meta-analysis of masking studies suggests that the detractors may have a point. The paper—a rigorous assessment of 78 studies—was published by Cochrane, an independent policy institution that has become well known for its reviews. The review’s authors found “little to no” evidence that masking at the population level reduced COVID infections, concluding that there is “uncertainty about the effects of face masks.” That result held when the researchers compared surgical masks with N95 masks, and when they compared surgical masks with nothing.

On Twitter, longtime critics of masking and mandates held this up as the proof they’d long waited for. The Washington Free Beacon, a conservative outlet, quoted a researcher who has called the analysis the “scientific nail in the coffin for mask mandates.” The vaccine skeptic Robert Malone used it to refute what he called “self-appointed ‘experts’” on masking. Some researchers weighed in with more nuanced interpretations, pointing out limitations in the review’s methods that made it difficult to draw firm conclusions. Even the CDC director, Rochelle Walensky, pushed back against the paper in a congressional testimony this week, citing its small sample size of COVID-specific studies. The argument is heated and technical, and probably won’t be resolved anytime soon. But the fact that the fight is ongoing makes clear that there still isn’t a firm answer to among the most crucial of pandemic questions: Just how effective are masks at stopping COVID?

An important feature of Cochrane reviews is that they look only at “randomized controlled trials,” considered the gold standard for certain types of research because they compare the impact of one intervention with another while tightly controlling for biases and confounding variables. The trials considered in the review compared groups of people who masked with those who didn’t in an effort to estimate how effective masking is at blunting the spread of COVID in a general population. The population-level detail is important: It indicates uncertainty about whether requiring everyone to wear a mask makes a difference in viral spread. This is different from the impact of individual masking, which has been better researched. Doctors, after all, routinely mask when they’re around sick patients and do not seem to be infected more often than anyone else. “We have fairly decent evidence that masks can protect the wearer,” Jennifer Nuzzo, an epidemiologist at Brown University, told me. “Where I think it sort of falls apart is relating that to the population level.”

The research on individual masking generally shows what we have come to expect: High-quality masks provide a physical barrier between the wearer and infectious particles, if worn correctly. For instance, in one study, N95 masks were shown to block 57 to 90 percent of particles, depending on how well they fit; cloth and surgical masks are less effective. The caveat is that much of that support came from laboratory research and observational studies, which don’t account for the messiness of real life.

That the Cochrane review reasonably challenges the effectiveness of population-level masking doesn’t mean the findings of previous studies in support of masking are moot. A common theme among criticisms of the review is that it considered only a small number of studies by virtue of Cochrane’s standards; there just aren’t that many randomized controlled trials on COVID and masks. In fact, most of those included in the review are about the impact of masking on other respiratory illnesses, namely the flu. Although some similarities between the viruses are likely, Nuzzo explained on Twitter, COVID-specific trials would be ideal.

The handful of trials in the review that focus on COVID don’t show strong support for masking. One, from Bangladesh, which looked at both cloth and surgical masks, found a 9 percent decrease in symptomatic cases in masked versus unmasked groups (and a reanalysis of that study found signs of bias in the way the data were collected and interpreted); another, from Denmark, suggested that surgical masks offered no statistically significant protection at all.

Criticisms of the review posit that it might have come to a different conclusion if more and better-quality studies had been available. The paper’s authors acknowledge that the trials they considered were prone to bias and didn’t control for inconsistent adherence to the interventions. “The low to moderate certainty of evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect,” they concluded. If high-quality masks worn properly work well at an individual level, after all, then it stands to reason that high-quality masks worn properly by many people in any situation should indeed provide some level of protection.

Tom Jefferson, the review’s lead author, did not respond to a request for comment. But in a recent interview about the controversy, he stood by the practical implications of the new study. “There’s still no evidence that masks are effective during a pandemic,” he said.

Squaring all of this uncertainty with the support for masking and mandates early in the pandemic is difficult. Evidence for it was scarce in the early days of the pandemic, Nuzzo acknowledged, but health officials had to act. Transmission was high, and the costs of masking were seen as low; it was not immediately clear how inconvenient and unmanageable masks could be, especially in settings such as schools. Mask mandates have largely expired in most places, but it doesn’t hurt most people to err on the side of caution. Nuzzo still wears a mask in high-risk environments. “Will that prevent me from ever getting COVID? No,” she said, but it reduces her risk—and that’s good enough.

What is most frustrating about this masking uncertainty is that the pandemic has presented many opportunities for the U.S. to gather stronger data on the effects of population-level masking, but those studies have not happened. Masking policies were made on sound but limited data, and when decisions are made that way, “you need to continually assess whether those assumptions are correct,” Nuzzo said—much like how NASA collects huge amounts of data to prepare for all the things that could go wrong with a shuttle launch. Unfortunately, she said, “we don’t have Houston for the pandemic.”

Obtaining stronger data is still possible, though it won’t be easy. A major challenge of studying the effect of population-level masking in the real world is that people aren’t good at wearing masks, which of course is a problem with the effectiveness of masks too. It would be straightforward enough if you could guarantee that participants wore their masks perfectly and consistently throughout the study period. But in the real world, masks fit poorly and slip off noses, and people are generally eager to take them off whenever possible.

Ideally, the research needed to gather strong data—about masks, and other lingering pandemic questions—would be conducted through the government. The U.K., for example, has funded large randomized controlled trials of COVID drugs such as molnupiravir. So far, that doesn’t seem to have happened in the U.S. None of the new studies on masking included in the Cochrane review were funded by the U.S. government. “The fact that we never as a country really set up studies to answer the most pressing questions is a failure,” said Nuzzo. What the CDC could do is organize and fund a research network to study COVID, much like the centers of excellence the agency has for fields such as food safety and tuberculosis.

The window of opportunity hasn’t closed yet. The Cochrane review, for all of its controversy, is a reminder that more research on masking is needed, if only to address whether pro-mask policies warrant the rage they incite. You would think that the policy makers who encouraged masking would have made finding that support a priority. “If you’re going to burn your political capital, it’d be nice to have the evidence to say that it’s necessary,” Nuzzo said.

At this point, even the strongest possible evidence is unlikely to change some people’s behavior, considering how politicized the mask debate has become. But as a country, the lack of conclusive evidence leaves us ill-prepared for the next viral outbreak—COVID or otherwise. The risk is still low, but bird flu is showing troubling signs that it could make the jump from animals to humans. If it does, should officials be telling everyone to mask up? That America has never amassed good evidence to show the effect of population-level masking for COVID, Nuzzo said, has been a missed opportunity. The best time to learn more about masking is before we are asked to do it again.

Yasmin Tayag

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February 13, 2023