Decoding Diabetes With Dr. Bob: The GLP-1 Revolution

In my lifetime, I have not seen anything revolutionize diabetes (and certainly obesity) care in the way GLP-1 receptor agonists have in the last few years. I’ve seen my own practice almost become a “GLP-1 clinic” for both people with type 2 diabetes and type 1 diabetes (off-label). 

About every other patient I see is on a GLP-1, though it’s worth noting that a significant stigma still exists around these drugs. When patients are interested in starting on one, they often sheepishly ask about it, not wanting to direct their care. But they get a big smile when I say, “Yes. That could be a great idea. Let’s talk about it.”

What makes the story of GLP-1s particularly interesting is that it started nearly 20 years ago with a twice-daily injection called Byetta, which offered modest A1C reduction and less than 10% weight loss. Five years later, a once-daily injection called Victoza became available, eventually followed by once-weekly injection options, Ozempic and Mounjaro, where the field currently stands. 

Arguably, these therapies really took off when the newest analogs demonstrated unprecedented degrees of weight loss and entered popular culture to an extent not seen since Viagra in the late 1990s. Demand for semaglutide (Ozempic) and tirzepatide (Mounjaro) has soared to the point of shortages, prompting multiple manufacturing site expansions. 

In addition, compounded (and counterfeit) versions can be found online – typically at a fraction of the cost of brand-name versions. This begs numerous questions about pricing: What financial impact will U.S. pricing impose on the individual and system levels, and how does that differ outside the U.S.? How will the robust pipeline of new therapies affect access? This is a complex challenge, and addressing it will likely involve figuring out how to better align the motivations of different stakeholders.

From past to present: explosive growth and adoption

GLP-1s did not show massive growth right from the start – it was only in the last few years that this drug class has skyrocketed. Ozempic is now the second-highest selling drug worldwide, a position no diabetes-related drug has ever seen, and second only to Merck’s Keytruda, an oncology compound.

Why is that the case? There are many drivers of this growth, including:

• The appeal of increased drug efficacy
• Improved side effect profile
• Greater obesity and diabetes prevalence
• Additional indications (e.g., heart, kidney, and liver health)
• Social media
• Cultural shifts toward greater acceptance of obesity as a disease

Over 12% of the U.S. adult population has used a GLP-1 – that’s over 30 million people. For adults aged 18-49, the leading reason for using a GLP-1 R is weight management. In contrast, older adults (ages 50 and older) more often reported using GLP-1s to treat diabetes. 

Naturally, with the physiological effects of aging, older adults are more likely to develop cardiovascular and metabolic diseases. It'll be interesting, though, to see whether fewer do in the future since younger adults are starting therapy (and highly effective therapy for that matter) before those conditions manifest. 

What’s next?

While it’s impossible to say what’s next for GLP-1s, they have certainly prompted shifts in the field and beyond. For researchers, the appeal of entering the GLP-1 arena persists, and the race is on to understand how else these drugs can be used – and their maximum potential. 

For people with diabetes, healthcare providers, and advocates, there are several challenges to address, such as the availability of these drugs, coverage, pricing, side effects, and more.    

Shifts in patient care and education

Virtually every drug has some sort of side effect, and GLP-1s are no exception. The most reported side effects are gastrointestinal in nature (e.g., nausea, vomiting). This makes sense given their ability to delay gastric emptying and reduce hunger or promote a feeling of fullness in the brain. 

Neurologically, a full stomach can prompt receptors to send signals to the brain, which then triggers nausea or vomiting as a protective response. For healthcare providers, the motto to minimize these side effects is to “start low and go slow.” This means starting at a low dose and slowly increasing it over time. In a similar vein, one tip I share with my patients is to eat slowly or stop halfway through the meal and, after around five minutes, see how full they are and then eat accordingly. 

When introducing people to GLP-1s, it is also important to set realistic expectations. For instance, weight loss is not immediate, especially at lower doses during the titration period. Typically, it can take several months to see the significant weight loss that these medications can provide. Additionally, treatment responses can vary – one person might not respond much (or at all), while another might be considered a “super-responder.”

Equally important is the need to facilitate behavior change. This is where digital health companies have started to pave the way by offering wraparound care. In addition to providing customers with GLP-1s, these companies offer 24/7 support and coaching. Some companies even offer strength training programs, not only promoting healthy behaviors, but also tackling muscle loss seen with GLP-1s.

Nutrition education is also an area that I think is particularly important for people with diabetes and healthcare providers to become well-versed in. For some people, taking a GLP-1 has helped reduce “food noise,” or constant, intrusive thoughts about food. Now, instead of devoting time during a visit to address food intake quantity, providers can focus on advising people about food intake quality. In addition, eating sufficient protein (0.8-1.5 g/kg of body weight per day, the higher range being for older adults) is critical to prevent the muscle loss that can occur with GLP-1 treatment.

Therefore, it’s especially important to advise people taking a GLP-1 on these nutritional recommendations. For those who may not be used to counting their daily protein intake, it can be helpful to offer tips and strategies or recommend that they see a dietitian.  

New indications and more players in the field

The number of indications for GLP-1s continues to grow steadily, like Ozempic’s recent approval for adults with type 2 diabetes and chronic kidney disease, as well as benefits beyond weight and blood sugar management (e.g., peripheral artery disease, liver disease, heart disease, sleep apnea, osteoarthritis). 

There has been a lot of buzz about what these drugs may be capable of, and you can see below, GLP-1s are being investigated in a range of conditions. 

Approved indications for GLP-1s:

• Cardiovascular disease
• Chronic kidney disease
• Obesity
• Sleep apnea
• Type 2 diabetes
• Metabolic dysfunction-associated steatohepatitis (MASH)

Potential future indications:
(indications with asterisks have already been investigated in randomized clinical trials)

• Substance use disorders (alcohol, tobacco)
• Alzheimer’s
• Parkinson’s
• Cancer prevention
• Diabetes prevention*
• Diabetic retinopathy
• Heart failure*
• Osteoarthritis*
• Peripheral artery disease*
• Polycystic ovarian syndrome
• Psoriasis

When I was at the ADA’s 85th Scientific Sessions this year, what was quite apparent was just how quickly the field has progressed beyond GLP-1s. Now there’s GLP-1/GIP dual agonism, GLP-2 agonism, glucagon agonism, GIP antagonism…the list goes on. To the general public, these are often all referred to as “Ozempic” or GLP-1s.

With these new combinations, we’re also seeing new features, such as ease of administration and dosing schedules (e.g., oral formulations and monthly dosing), and side effect mitigation (e.g., muscle preservation). There are literally dozens of new compounds and over 150 clinical trials underway. While GLP-1s seem almost unstoppable now, it’s important to recognize that they may not be a cure-all. That said, there is still so much to celebrate and look forward to about them. 

There has also been recent research highlighting the safe and effective use of these therapies in type 1 diabetes, especially in combination with automated insulin delivery (AID). As someone who has prescribed GLP-1s for people with type 1 diabetes for years, I could not have been more excited to see data on this and can only hope this will lead to new FDA indications and broader payer coverage. Safety concerns will be important to address, and clinician and patient education on this front will be crucial (e.g., how to adjust insulin doses and manage side effects). 

How do providers sort through all the options?

The emerging challenge with all this progress on new therapies in the pipeline is how healthcare providers sort through their options when treating patients. Although many therapies in development will not come to market, I believe most will. That said, there will be many options, and the question is, how will clinician behavior be affected? 

In all likelihood, clinicians will probably continue to use the big two (semaglutide and tirzepatide) for people who can access and afford them. It may take a while for the other drugs to gain traction unless there are dramatic marketing efforts for them or they have some obvious advantage (e.g., oral administration). Even so, providers will be faced with the challenge of weighing the pros and cons of available treatment options. 

Looking forward: What can we do now?

One major unanswered question on my mind, and perhaps yours too, is why so many people (more than 50%) stop treatment within a year. There are many theories out there, including side effects, cost, access, stigma, perceived need, and fear of long-term effects – and it’s likely that more than one theory is at play. So, where should we target our efforts first?

The information needed to answer this question might already lie in some large datasets waiting to be analyzed. But once we have an answer, where do we go from there? For example, if side effects are the main reason for discontinuation, would lower doses maybe work for weight maintenance? Would better personalized communication through digital health outreach also be effective? Answering these questions will benefit not only people taking these medications but also drug developers as they work toward more effective, safe, and tolerable therapies.

The information and insights in this column are adapted from an original Closer Look column, published by Close Concerns. Written by Dr. Bob and Elaine Young, this column was originally designed for clinicians, researchers, and professionals working in diabetes and obesity care and has been adapted for diaTribe audiences.

Read more installments of Decoding Diabetes With Dr. Bob here:

• Meet Dr. Bob
• Diabetes and Mental Health