In December 1921, Leonard Thompson was admitted to Toronto General Hospital so weak and emaciated that his father had to carry him inside. Thompson was barely a teenager, weighing all of 65 pounds, dying of diabetes. With so little to lose, he was an ideal candidate to be patient No. 1 for a trial of the pancreatic extract that would come to be called insulin.
The insulin did what today we know it can. “The boy became brighter, more active, looked better and said he felt stronger,” the team of Toronto researchers and physicians reported in March 1922 in
Chris Feudtner, a pediatrician, medical historian, and medical ethicist at the University of Pennsylvania, has described this hormonal regulation of fuel partitioning as that of a “Council of Food Utilization.” Organs communicate with one another “via the language of hormones,” he wrote in Bittersweet, his history of the early years of insulin therapy and the transformation of type 1 diabetes from an acute to a chronic disease. “The rest of the body’s tissues listen to this ongoing discussion and react to the overall pattern of hormonal messages. The food is then used—for burning, growing, converting, storing, or retrieving.” Perturb that harmonious discourse, and the whole physiological ensemble of the human body reverberates with corrections and counter-corrections.
This is why the long-term consequences of using these drugs can be so difficult to fathom. Insulin therapy, for instance, did not just lower patients’ blood sugar; it restored their weight and then made them fatter still (even as it inhibited the voracious hunger that was a symptom of uncontrolled diabetes). Insulin therapy may also be responsible, at least in part, for diabetic complications—atherosclerosis and high blood pressure, for instance. That possibility has been acknowledged in textbooks and journal articles but never settled as a scientific matter.
With the discovery of insulin and its remarkable efficacy for treating type 1 diabetes, diabetologists came to embrace a therapeutic philosophy that is still ascendant today: Treat the immediate symptoms of the disease with drug therapy and assume that whatever the future complications, they can be treated by other drug or surgical therapies. Patients with diabetes who develop atherosclerosis may extend their lives with stents; those with hypertension may go on blood-pressure-lowering medications.
A similar pattern could emerge for people taking GLP-1s. (We see it already in the prospect of drug therapies for GLP-1-related muscle loss.) But the many clinical trials of the new obesity treatments do not and cannot look at what might happen over a decade or more of steady use, or what might happen if the injections must be discontinued after that long. We take for granted that if serious problems do emerge, far down that distant road, or if the drugs have to be discontinued because of side effects, newer treatments will be available to solve the problems or take over the job of weight maintenance.
In the meantime, young patients who stick with treatment can expect to be on their GLP-1s for half a century. What might happen during those decades—and what might happen if and when they have to discontinue use—is currently unknowable, although, at the risk of sounding ominous, we will find out.
Pregnancy is another scenario that should generate serious questions. A recently published study found no elevated risk of birth defects among women taking GLP-1 agonists for diabetes right before or during early pregnancy, as compared with those taking insulin, but birth defects are just one obvious and easily observable effect of a drug taken during pregnancy. Children of a mother with diabetes or obesity tend to be born larger and have a higher risk of developing obesity or diabetes themselves later in life. The use of GLP-1 agonists during pregnancy may reduce—or exacerbate—that risk. Should the drugs be discontinued before or during pregnancy, any sudden weight gain (or regain) by the mother could similarly affect the health of her child. The consequences cannot be foreseen and might not manifest themselves until these children reach their adult years.
The rise of GLP-1 drugs may also distort our understanding of obesity itself, in much the way that insulin therapy distorted the thinking in diabetes research. With insulin’s discovery, physicians assumed that all diabetes was an insulin-deficiency disorder, even though this is true today for only 5 to 10 percent of diabetic patients, those with type 1. It took until the 1960s for specialists to accept that type 2 diabetes was a very different disorder—a physiological resistance to insulin, inducing the pancreas to respond by secreting too much of the hormone rather than not enough. And although the prognosis today for a newly diagnosed patient with type 2 diabetes is better than ever, physicians have yet to establish whether the progression and long-term complications of the disease are truly inevitable, or whether they might be, in fact, a consequence of the insulin and other drug therapies that are used to control blood sugar, and perhaps even of the diets that patients are encouraged to eat to accommodate these drug therapies.
Already, assumptions are being made about the mechanisms of GLP-1 agonists without the rigorous testing necessary to assess their validity. They’re broadly understood to work by inhibiting hunger and slowing the passage of food from the stomach—effects that sound benign, as if the drugs were little more than pharmacological versions of a fiber-rich diet. But changes to a patient’s appetite and rate of gastric emptying only happen to be easy to observe and study; they do not necessarily reflect the drugs’ most important or direct actions in the body.
When I spoke with Chris Feudtner about these issues, we returned repeatedly to the concept that Donald Rumsfeld captured so well with his framing of situational uncertainty: the known unknowns and the unknown unknowns. “This isn’t a you-take-it-once-and-then-you’re-done drug,” Feudtner said. “This is a new lifestyle, a new maintenance. We have to look down the road a bit with our patients to help them think through some of the future consequences.”
Patients, understandably, may have little time for a lecture on all that we don’t know about these drugs. Obesity itself comes with so many burdens—health-related, psychological, and social—that deciding, after a lifetime of struggle, to take these drugs in spite of potential harms can always seem a reasonable choice. History tells us, though, that physicians and their patients should be wary as they try to balance known benefits against a future, however distant, of unknown risk.
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