The changing landscape of endocrinology: GLP-1s, new diabetes technology and more
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The field of endocrinology saw many advancements in 2024 and more developments and innovations are anticipated in 2025.
Healio | Endocrine Today asked members of the Editorial Board and other experts their opinion on the leading topics in endocrinology heading into 2025.
Source: Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, FADCES, FCCP. Printed with permission.
A common thread in the responses received was the diabetes, weight-loss and other benefits of GLP-1 receptor agonists. In the past year, there was news about the prevention of progression to diabetes with tirzepatide (Mounjaro/Zepbound, Eli Lilly), benefits of tirzepatide and semaglutide (Ozempic/Wegovy, Novo Nordisk) in other patient populations such as those with heart failure and chronic kidney disease, and mounting evidence for the triple-hormone agonist retatrutide (Eli Lilly). But this news was also coupled with concerns about the safety of GLP-1s formulated by compounding pharmacies in response to shortages from manufacturers, issues with access to the drugs due to high cost and loss of muscle mass.
Other topics highlighted include advances in continuous glucose monitoring, the appropriateness of triiodothyronine/thyroxine therapy for patients with hypothyroidism not optimally treated with levothyroxine, upcoming guidelines from the American Thyroid Association and strides being made in preserving beta-cell function in patients with type 1 diabetes.
Question: What are some of the most important advances or issues in endocrinology today?
Louis J. Aronne, MD, FACP, FTOS, DABOM
I am biased because I am one of the authors of this paper, but this must be mentioned because it is a new record: In the SURMOUNT-1 trial, after 3 years of treatment with tirzepatide, we were able to reduce the incidence of diabetes by 94% in people who started with prediabetes. In some subgroups, it was reduced by as much as 99%.
It looks like type 2 diabetes may be completely preventable. People have talked about this over the years, but we have now done that, for all intents and purposes. I am not saying that no one will ever develop diabetes again, but this accomplishment makes me very optimistic for the future that we will be able to manage patients a lot better. When I was a medical student, diabetes often meant going blind or having your leg amputated. It was a horror show. It has gotten better as the years have gone on as we have recognized that earlier treatment can prevent those kinds of consequences. We now have the potential to prevent someone from even having diabetes. That is really something.
As part of the trial, we did a mediation analysis to determine what is causing what. A slight majority of the effect was from weight loss, but there was also a potent effect from the medication. In 2023, the SELECT trial showed that we could reduce the risk for heart attack, stroke and death using semaglutide 2.4 mg. That trial also showed a substantial reduction in risk for developing type 2 diabetes, by about 73%. So, we have seen this coming over the years. But SURMOUNT-1, in my opinion, is the best result we have ever seen.
Another major development has been the recognition that the chronic diseases that are complications of obesity can be treated by using the GLP-1 or GLP-1/GIP dual agonists. For example, the SURMOUNT-OSA trial in which tirzepatide produced 20% weight loss showed that it was almost as effective as continuous positive airway pressure in managing sleep apnea; it has since been approved for this indication. Other complications which have recently been shown to benefit from treatment with these drugs are heart failure with preserved ejection fraction (STEP HFpEF DM), kidney failure (FLOW) and osteoarthritis (STEP 9) all with semaglutide, and the SUMMIT trial utilizing tirzepatide in patients with HFpEF. Finally, the obesity paradox appears to have been dispelled. The obesity paradox stated that people with excess weight were at less risk for certain disease states; they were somehow protected by the increase in body weight. People in the field of obesity treatment did not agree with that. But in cardiology, some specialists, particularly in heart failure, believed in the obesity paradox. We now have trials showing that if you have heart failure and lose weight with these compounds, your risk for a bad outcome is reduced, once and for all disproving the obesity paradox. So, what explains the obesity paradox phenomenon? It could be due to sarcopenia in those with heart failure and a resulting lower weight, or the inaccuracy of BMI as a measure of risk. But it is not because someone has more body fat. An increase in muscle mass could potentially be protective, or a measure of lower risk.
Aronne is the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine.
Susan Cornell, PharmD, CDCES, FAPhA, FADCES
In the post-era of cardiovascular outcome trials (CVOTs), the evidence continues to mount regarding the benefits beyond glucose lowering with GLP-1 receptor agonists. So much so that numerous clinical guidelines have changed based on the CVOT data. Several agents within this class of medications boast CV risk reduction, potential renoprotective benefits and, most notably, weight loss.
The notoriety of the GLP-1s skyrocketed when nearly every media outlet, as well as non-health care influencers, created an enormous buzz around their weight-loss benefits, specifically for semaglutide and tirzepatide. Until recently, this high demand for GLP-1 medications created a drug shortage. During the shortage, patients and clinicians sought non-FDA-approved compounded GLP-1s for a quick-fix solution.
The concern with non-FDA-approved compounded GLP-1s is multifactorial.
- No. 1, is this legal? When a drug is in shortage, compounders may be able to prepare a compounded version of that drug if they meet certain requirements in the Federal Food, Drug, and Cosmetic Act.
- No. 2, if the pharmaceutical company does not have the supply to keep up with the demand, where are the compounders getting the product from? It is important to know that compounded GLP-1 products are not reviewed by the FDA, meaning there is less rigorous oversight compared with brand-name products. Therefore, what is the safety and efficacy with compounded products? Compounding pharmacies can purchase the GLP-1 powder from registered wholesalers who have documentation that the active pharmaceutical ingredient comes from an FDA-registered manufacturer and the compounded product is prepared to the standards of a United States Pharmacopeia (USP) monograph. However, concerns have been identified in some of the compounded products evaluated that include an unacceptably high level of impurities in tested samples, the actual strength of the product being lower than what is on the label and use of salt forms not permitted by federal law. These inaccuracies can increase the risk for harm to the patient.
- No. 3, what additives (other ingredients) are used in preparation? Since a compounded drug is not an exact copy of the brand name, what effect can that have on the patient? Compounding pharmacies may use additives in the “copycat” product that suggest “additional benefits,” such as B vitamins or antinausea agents. The worry is that these additives can reduce sterility of the active product and lead to contamination and safety issues.
- No. 4, are compounded products the same as counterfeit products? No, products compounded in a licensed, reputable pharmacy can be safe to use, especially if the compounding pharmacy is obtaining quality products and preparing it by the USP standards. However, there are counterfeit products in the drug supply chain. These unscrupulous compounds can look identical to brand-name formulations. Reports have also noted that some counterfeit products contained insulin instead of a GLP-1, resulting in severe hypoglycemia, and also that some needles accompanying the GLP-1 pen were not sterile, increasing the risk for infection.
So now that the GLP-1 drug shortage has been abated, should copycat compounds continue to be available? The safe answer is to continue with a brand you can trust, whether a brand-name product or a trusted pharmacist that is following the USP monograph. With the uncertainty of copycat compounded products, patients and clinicians need to be alert and aware of what is being injected into the body.
Cornell is director of experiential education and professor of pharmacy practice at Midwestern University College of Pharmacy in Downers Grove, Illinois, and a member of the Healio | Endocrine Today Editorial Board.
Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, FADCES, FCCP
In 2025, I forecast an explosion of diabetes technology for people with type 2 diabetes. For the first time ever, we have an over-the-counter CGM available. This means that people do not need a prescription and can readily access these devices. This will allow nearly any adult to purchase a CGM without needing to meet any specific criteria. The Stelo Glucose Biosensor System (Dexcom) is geared toward people with type 2 diabetes or even prediabetes not on insulin therapy since it doesn’t have typical CGM alerts and does not show readings below 70 mg/dL. The Lingo biosensor (Abbott), which was advertised at the Chicago Marathon, is geared toward athletes. Libre Rio (Abbott) is also anticipated to be available in 2025 as an OTC option geared toward people with type 2 diabetes. As more people are exposed to CGM, they are likely to purchase it OTC, or at least ask their health care team about it. This will lead to more CGM exposure and use in primary care practices. It may take some effort to figure out optimal workflows for prescribing, retrieving and interpreting data, but this is likely to lead to better quality care for people with diabetes.
Another exciting advancement regarding CGM is the Eversense 365 (Ascensia Diabetes Care), which is an implantable CGM that can be worn for an entire year and requires only-weekly calibration. This is a nice upgrade from the previous version, which was 180 days, and the original, which was only 90 days. This is a product that can help people with type 1 diabetes or type 2 diabetes, especially those who have been disappointed with other sensors due to reasons like skin sensitivity, sensors falling off or compression lows, all which are unlikely to occur with this new product.
Additionally, insulin pumps are no longer just for people with type 1 diabetes. It was exciting to see Omnipod 5 (Insulet) gain FDA approval for type 2 diabetes. More companies are likely to gain approval for this indication in the near future as well. While many of us have been using it off-label in this population, this means the company is now able to talk to health care professionals and advertise this new indication. More people with type 2 diabetes will likely hear about the pump and recognize that they could be candidates. This may allow it to expand beyond endocrine clinics, although education and training will still be important. With Omnipod 5 available through the pharmacy route, it is generally easier to obtain since there is not a long contract or additional lab requirements. More insulin pumps are expected to go through the pharmacy, including a new automated insulin delivery system (twiist, Sequel Med Tech), which will have the lowest glucose target of 87 mg/dL. Although not FDA-approved for type 1 diabetes, if there are not C-peptide requirements, people with type 2 diabetes may be able to get the twiist and any other pumps offered through the pharmacy.
Ultimately, all this technology has the potential to improve quality of life and achieve glycemic targets. Between the GLP-1s and all of the diabetes technology, I am optimistic that diabetes complications will go way down, and quality of life will go way up.
Isaacs is an endocrine clinical pharmacy specialist and co-director of Endocrine Disorders in Pregnancy at Cleveland Clinic Endocrinology & Metabolism Institute and a member of the Healio | Endocrine Today Editorial Board.
Stephanie Kim, MD, MPH, and Irl B. Hirsch, MD
Over the last several years, GLP-1s have gained popularity and become household names. Their glycemic and cardiorenal benefits in patients with type 2 diabetes, along with weight-loss effects, are well established. Recent studies have also indicated additional advantages, including reductions in alcohol and drug addiction and lower risk for cognitive decline and dementia. Not surprisingly, GLP-1 use has increased, as a study of 45 million U.S. patient records found 1 million new users from 2011 to 2023; these drugs are also used frequently off-label in patients with type 1 diabetes.
Underserved populations have higher rates of type 2 diabetes, obesity and related comorbidities and would benefit the most from GLP-1s, but face the greatest barriers to accessing and affording these medications. Reports have shown disparities in GLP-1 use including higher usage among non-Hispanic white individuals and lower usage among Mexican American individuals and uninsured people. This highlights the persistent inequalities that have long plagued our health care system, with cost being a major limiting factor.
According to a 2023 Kaiser Family Foundation report, the monthly list price of injectable semaglutide was about $900 in the U.S., compared with approximately $150 and $80 in Canada and France, respectively. However, the estimated monthly cost-based price to manufacture GLP-1s in the U.S. was found to be between 75 cents and $72.50. This raises the question: Why are these medications so expensive in the U.S.? The CEO of Novo Nordisk, the manufacturer of semaglutide, attributed the high costs to pharmacy benefit managers (PBMs) and insurers at a 2024 Senate committee hearing. Multiple factors contribute to the lack of affordability of prescription drugs in the U.S.; perhaps the most significant is the lack of transparency in negotiations with PBMs, unlike in other countries where negotiations are conducted directly with the government.
If this sounds familiar, it is because we have faced similar challenges with insulin pricing. Fortunately, in recent years, we have seen progress in improving the accessibility and affordability of insulin, though it literally took an act of Congress to achieve this. The Inflation Reduction Act of 2023 introduced a $35 monthly insulin cap for Medicare beneficiaries, and many states have implemented their own caps. Additionally, insulin manufacturers have set monthly copays at $35 for eligible patients. The Medicare Drug Price Negotiation Program for 2026 includes certain insulins and other diabetes medications but notably excludes GLP-1s.
What will it take to attain price reductions for GLP-1s like those seen with insulin? We need comparable backing from our government and drug manufacturers to enforce stricter regulations on PBMs. Although GLP-1s are not regarded as directly “lifesaving” as insulin, their importance for their four indications — glycemia, obesity, cardiac disease and renal disease — cannot be overstated. While the cost-effectiveness of semaglutide has been suggested, this should not be mistaken for affordability. Although there have been advancements in insulin affordability, we must advocate for expanded coverage of GLP-1s, which have revolutionized the treatment of type 2 diabetes and obesity. Our goal is to ensure equitable access for all patients with diabetes.
Kim is an endocrinologist at University of Washington School of Medicine (UW Medicine) in Seattle. Hirsch is professor of medicine at UW Medicine.
Mary-Elizabeth Patti, MD
The exciting explosion of clinical and research advances related to incretins, including the single-, dual- or upcoming triple-agonist approaches, will likely continue over the next few years. While efficacy for diabetes and obesity receives the most attention, the robust prevention of diabetes after 3 years of use in the SURMOUNT-1 trial was truly amazing and could contribute to a profound shift in our ability to not only treat, but also prevent, type 2 diabetes.
Of course, further studies addressing “real world” efficacy and side effect profiles, including loss of muscle mass with chronic therapy, are required. We still need to identify which patient populations will benefit the most for long-term health outcomes, especially if costs remain so high.
The use of these medications to improve other endpoints beyond diabetes and obesity parameters, whether sleep apnea, liver outcomes, CVD or kidney endpoints, is also remarkable. I look forward to seeing phase 3 data for the even more potent triple agonist retatrutide in the near future.
Another hot topic is the need to consider the balance between metabolic surgery and emerging incretin-based medical therapies for obesity and type 2 diabetes. How do we balance the demonstrated sustained impact of surgical therapy against medical therapies for which long-term efficacy remains uncertain? What is the cost effectiveness of each approach within different populations?
There is also excitement around type 1 diabetes, particularly the emerging evidence that preservation of beta-cell function is possible. Until we achieve this dream, the implementation of effective diabetes technology in younger and younger populations is encouraging.
There is growing awareness that we need to consider social determinants of health no matter what the topic, whether it be type 2 diabetes prevention, type 2 diabetes treatment, obesity treatment, type 1 diabetes prevention or use of technology. Emerging data in all of those areas demonstrate that socioeconomic status and other determinants of health influence response rates, and understanding the mechanisms responsible for these differences is essential to effect positive change within all our communities.
Using RNA interference as a therapeutic tool for metabolic disease is also an exciting area. Recent clinical studies have shown that messenger RNA itself or small interfering RNA or antisense oligonucleotides can be used as a potent treatment for hyperlipidemia. Since treatment of hyperlipidemia is a cornerstone of prevention of cardiovascular disease in individuals with diabetes, these advances will likely have major clinical impact. Moreover, it is likely that we will see the emergence of similar strategies for other aspects of metabolic disease.
Patti is senior investigator and adult endocrinologist at Joslin Diabetes Center and associate professor of medicine at Harvard Medical School.
Elizabeth N. Pearce, MD, MSc
Whether or not patients with hypothyroidism who feel unwell on levothyroxine monotherapy benefit from combined T3/T4 therapy has been highly controversial.
Studies consistently report that about 15% of patients have persistent symptoms on levothyroxine alone, even when serum thyroid-stimulating hormone levels are optimized. It has been hypothesized that individuals with polymorphisms in the type 2 deiodinase gene — who have decreased conversion of T4 to the active hormone T3 — may be at increased risk for persistent hypothyroid symptoms on levothyroxine therapy. Many trials have been published over the last 2 decades, but most have been underpowered and/or have failed to target patient populations with symptoms at baseline, and results overall have been inconclusive.
I would anticipate that this question will continue to be the subject of intense debate over the next year. While definitive answers likely will not be forthcoming in 2025, a randomized, multicenter clinical trial is currently underway in the Netherlands that specifically seeks to determine whether T3/T4 combination therapy improves symptoms in adult patients who have persistent severe fatigue at baseline despite normal TSH levels on levothyroxine alone. In addition, the ATA has begun the process of revising current clinical practice guidelines for hypothyroidism. Hopefully, more definitive evidence-based recommendations for patients with hypothyroidism are on the horizon.
The upcoming year will see the publication of two long-awaited ATA guideline updates: one for the management of thyroid nodules and one for the management of differentiated thyroid cancer. The last revision was published in 2015, and there have been a huge amount of new data since then to inform clinical practice. The nodule guideline is expected to provide expanded ultrasonographic risk stratification parameters, still using a pattern-based approach, rather than a point-based system such as the Thyroid Imaging, Reporting and Data System (TI-RADS). Among other changes, the differentiated cancer update is expected to provide new guidance about employing active surveillance for low-risk patients with thyroid cancer who elect monitoring rather than thyroid surgery. For the first time, a separate risk stratification system will be provided for oncocytic thyroid cancer, which had previously been lumped as a subset of follicular thyroid cancer. There will be increased incorporation of molecular test results in preoperative and postoperative decision-making. In addition, there will be new guidance for the de-escalation of monitoring in patients with low-risk tumors. Overall, I look forward to incorporating these new approaches in my own practice.
Pearce is professor of medicine in the section of endocrinology, diabetes and nutrition at Boston University Chobanian & Avedisian School of Medicine and a member of the Healio | Endocrine Today Editorial Board.
- References:
- Amin K, et al. How do prices of drugs for weight loss in the U.S. compare to peer nations’ prices? Peterson-KFF Health System Tracker. https://www.healthsystemtracker.org/brief/prices-of-drugs-for-weight-loss-in-the-us-and-peer-nations. Published Aug. 17, 2023. Accessed Oct. 25, 2024.
- Barber MJ, et al. JAMA Netw Open. 2024; doi:10.1001/jamanetworkopen.2024.3474.
- Giorgi RD, et al. eClinicalMedicine. 2024; doi:10.1016/j.eclinm.2024.102726.
- Hu Y, et al. Ann Transl Med. 2022;doi:10.21037/atm-22-200.
- Jastebroff AM, et al. N Engl J Med. 2024; doi:10.1056/NEJMoa2410819.
- Li P, et al. JAMA. 2024;doi:10.1001/jama.2024.18581.
- Limonte CP, et al. J Diabetes Complications. 2022;doi:10.1016/j.jdiacomp.2022.108204.
- Lincoff AM, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2307563.
- Qeadan F, et al. Addiction. 2024;doi:10.1111/add.16679.
- Yeo YH, et al. Ann Intern Med. 2024;doi:10.7326/M24-0019.
- For more information:
- Louis J. Aronne, MD, FACP, FTOS, DABOM, can be reached at ljaronne@med.cornell.edu; X (Twitter): @ljaronne.
- Susan Cornell, PharmD, CDCES, FAPhA, FADCES, can be reached at scorne@midwestern.edu.
- Irl B. Hirsch, MD, can be reached at ihirsch@uw.edu.
- Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, FADCES, FCCP, can be reached at dianamisaacs@gmail.com; X (Twitter): @dianamisaacs.
- Stephanie Kim, MD, MPH, can be reached at kimsteph@uw.edu.
- Mary-Elizabeth Patti, MD, can be reached at mary.elizabeth.patti@joslin.harvard.edu.
- Elizabeth N. Pearce, MD, MSc, can be reached at elizabeth.pearce@bmc.org.
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