There are many holy grails in medicine, with failure after
failure, like finding a way to prevent Alzheimer's disease or a non-invasive
means for accurately measuring ambulatory blood pressure. But one of the
biggest and most daunting has been finding drugs that can tackle obesity —
achieving a substantial amount of weight loss without serious side effects.
Many attempts to get there now fill a graveyard of failed drugs, such as
fen-phen in the 1990s when a single small study of this drug combination in 121
people unleashed millions of prescriptions, some leading to serious heart valve
lesions that resulted in withdrawal of the drug in 1995. The drug rimonabant,
an endocannabinoid receptor blocker (think of blocking the munchies after
marijuana) looked encouraging in randomized trials. However, subsequently, in a
trial that I led of nearly 19,000 participants in 42 countries around the
world, there was a significant excess of depression, neuropsychiatric
side-effects and suicidal ideation which spelled the end of that drug's life.
In the United States, where there had not been an
anti-obesity drug approved by the FDA since 2014, Wegovy (semaglutide), a
once-weekly injection was approved in June 2021. The same drug, at a lower
dose, is known as Ozempic (as in O-O-O, Ozempic, the ubiquitous commercial that
you undoubtedly hear and see on TV) and had already been approved in January
2020 for improving glucose regulation in diabetes. The next drug on fast track
at FDA to be imminently approved is tirzepatide (Mounjaro) following its
approval for diabetes in May 2022. It is noteworthy that the discovery of these
drugs for weight loss was serendipitous: they were being developed for
improving glucose regulation and unexpectedly were found to achieve significant
weight reduction.
Both semaglutide and tirzepatide underwent randomized,
placebo-controlled trials for obesity, with marked reduction of weight as shown
below. Tirzepatide at dose of 10 to 15 mg per week achieved >20% body weight
reduction. Semaglutide at a dose of 2.4 mg achieved ~17% reduction. These per
cent changes in body weight are 7-9 fold more than seen with placebo (2-3%
reduction). Note: these levels of per cent body weight reduction resemble what
is typically achieved with the different types of bariatric surgery, such as
gastric bypass.
Another way to present the data for the 2 trials is shown
here, with an edge for tirzepatide at high (10-15 mg) doses, extending to
>25% body weight reduction.
The results with semaglutide were extended to teens in a
randomized trial (as shown below), and a similar trial with tirzepatide is in
progress.
How Do These Drugs Work?
These are peptides in the class of incretins, mimicking gut
hormones that are secreted after food intake which stimulate insulin secretion.
These 2 drugs have in common long half-lives (~ 5 days),
which affords once-weekly dosing, but have different mechanisms of action.
Semaglutide activates (an agonist) the GLP-1 receptor, while tirzepatide is in
a new class of dual agonists: it activates (mimics) both the GLP-1 receptor and
GIP receptors (Gastric inhibit polypeptide is also known as glucose-dependent
insulinotropic polypeptide.) The potency of activation for tirzepatide is
5-fold more for GIPR than GLP1. As seen below, there are body wide effects that
include the brain, liver, pancreas, stomach, intestine, skeletal muscle and fat
tissue. While their mode of action is somewhat different, their clinical
effects are overlapping, which include enhancing satiety, delaying gastric
emptying, increasing insulin and its sensitivity, decreasing glucagon, and, of
course, reducing high glucose levels. The overlap extends to side effects of
nausea, vomiting, abdominal pain, constipation and diarrhea. Yet only 4 to 6%
of participants discontinued the drug in these trials, mostly owing to these GI
side effects (and 1-2% in the placebo group discontinued the study drug for the
same reasons).
In randomized trials among people with Type 2 diabetes, the
drugs achieved HbA1c reduction of at least an absolute 2 percentage points
which led to their FDA approvals (For semaglutide in January 2020, and for
tirzepatide in May 2022). The edge that tirzepatide has exhibited for weight
loss reduction may be related to its dual agonist role, but the enhancement via
GIP receptor activation is not fully resolved (as seen below with GIP?
designation). The Amgen drug in development (AMG-133) has a marked weight loss
effect but inhibits GIP rather than mimics it, clouding our precise
understanding of the mechanism.
The gut-brain regulation of food intake with the many gut
hormones (including leptin, gherlin, PYY, amylin) and targets in the body and
brain regions. From Muller et al, Nature Reviews Drug Discovery March 2022.
Nevertheless, when the two drugs were directly compared in a
randomized trial for improving glucose regulation, tirzepatide was superior to
semaglutide, as shown below. Of note, both drugs achieved very favorable
effects on lipids, reducing triglycerides, LDL and raising HDL cholesterol,
along with reduction of blood pressure, an outgrowth of the indirect effect of
weight reduction and direct metabolic effects of the drugs.
While there has been a concern about other side effects
besides the GI ones noted above, review of all the trials to date in these
classes of medication do not reinforce a risk of acute pancreatitis. Other rare
side effects that have been noted with these drugs include allergic reactions,
gallstones (which can occur with a large amount of weight loss), and potential
of medullary thyroid cancer (so far only documented in rats, not people), which
is why they are contraindicated in people with Type 2 multiple endocrine
neoplasia syndrome.
How They Are Given and Practical Considerations
For semaglutide, which has FDA approval, the indication is a
BMI of 30 kg/m2 or greater than 27 kg/m2 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, ~$1500 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 are obese and 13% of the 8
billion world's population (including over 340 million ages 5-18) is obese —
that sums us to over 1 billion people. 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 PCSK-9 inhibitors for
hypercholesterolemia or the TNF 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 to 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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