How they are given and practical considerations
For semaglutide, which has FDA approval, the indication is a body mass index of 30 kg/m2 or greater than 27 and a weight-related medical condition (such as hypertension, hypercholesterolemia, or diabetes). To reduce the GI side effects, which mainly occur in the early dose escalation period, semaglutide is given in increasing doses by a prefilled pen by self-injection under the skin (abdomen, thigh, or arm) starting at 0.25 mg for a month and gradual increases each month reaching the maximum dose of 2.4 mg at month 5. The FDA label for dosing of tirzepatide has not been provided yet but in the weight loss trial there was a similar dose escalation from 2.5 mg up to 15 mg by month 5. The escalation is essential to reduce the frequent GI side effects, such as seen below in the tirzepatide trial.
Semaglutide is very expensive, about $1,500 per month, and not covered by Medicare. There are manufacturer starter coupons from Novo Nordisk, but that is just for the first month. These drugs have to be taken for a year to 18 months to have their full effect and without changes in lifestyle that are durable, it is likely that weight will be regained after stopping them.
What does this mean?
More than 650 million adults and 340 million children aged 5-18 are obese. The global obesity epidemic has been relentless, worsening each year, and a driver of “diabesity,” the combined dual epidemic. We now have a breakthrough class of drugs that can achieve profound weight loss equivalent to bariatric surgery, along with the side benefits of reducing cardiovascular risk factors (hypertension and hyperlipidemia), improving glucose regulation, reversing fatty liver, and the many detrimental long-term effects of obesity such as osteoarthritis and various cancers. That, in itself, is remarkable. Revolutionary.
But the downsides are also obvious. Self-injections, even though they are once a week, are not palatable for many. We have seen far more of these injectables in recent years such as the proprotein convertase subtilisin/kexin type 9 inhibitors for hypercholesterolemia or the tumor necrosis factor blockers for autoimmune conditions. That still will not make them a popular item for such an enormous population of potential users.
That brings me to Rybelsus, the oral form of semaglutide, which is approved for glucose regulation improvement but not obesity. It effects for weight loss have been modest, compared with Wegovy (5 to 8 pounds for the 7- and 14-mg dose, respectively). But the potential for the very high efficacy of an injectable to be achievable via a pill represents an important path going forward—it could help markedly reduce the cost and uptake.
The problem of discontinuation of the drugs is big, since there are limited data and the likelihood is that the weight will be regained unless there are substantial changes in lifestyle. We know how hard it is to durably achieve such changes, along with the undesirability (and uncertainty with respect to unknown side effects) of having to take injectable drugs for many years, no less the cost of doing that.
The cost of these drugs will clearly and profoundly exacerbate inequities, since they are eminently affordable by the rich, but the need is extreme among the indigent. We’ve already seen celebrities take Wegovy for weight loss who are not obese, a window into how these drugs can and will be used without supportive data. As one physician recently observed, “Other than Viagra and Botox, I’ve seen no other medication so quickly become part of modern culture’s social vernacular.” Already there are concerns that such use is preventing access to the drugs for those who qualify and need them.
There are multiple agents in the class under development which should help increase competition and reduce cost, but they will remain expensive. There is private insurance reimbursement, often with a significant copay, for people who tightly fit the inclusion criteria. Eventual coverage by Medicare will markedly expand their use, and we can expect cost-effectiveness studies to be published showing how much saving there is for the drugs compared with bariatric surgery or not achieving the weight loss. But that doesn’t change the cost at the societal level. Even as we’ve seen with generics, which will ultimately be available, the alleviation of the cost problem isn’t what we’d hoped.
This is not unlike the recent triumphs of gene therapy, as in $3.5 million for a cure of hemophilia that just got FDA approval, but instead of a rare disease we are talking about the most common medical condition in the world. We finally get across the long sought after (what many would qualify as miraculous) goal line, but the economics collide with the uptake and real benefit.
These concerns can’t be put aside in the health inequity-laden world we live in, that will unquestionably be exacerbated. However, we cannot miss that this represents one of the most important, biggest medical breakthroughs in history. This may signify the end or marked reduction in the need for bariatric surgery. These drugs will likely become some of the most prescribed of all medications in the upcoming years. While there are many drawbacks, we shouldn’t miss such an extraordinary advance in medicine – the first real, potent and safe treatment of obesity.
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Dr. Topol is director, Scripps Translational Science Institute; executive vice president and professor of molecular medicine at The Scripps Research Institute and senior consultant, division of cardiovascular diseases, at the Scripps Clinic, both in La Jolla, Calif. He disclosed relevant financial relationships with Dexcom, Illumina, Molecular Stethoscope, Walgreens, Quest Diagnostics, MyoKardia, and National Institutes of Health. A version of this article first appeared on Medscape.com.