Side Effects are Limiting GLP-1 Drug Efficacy: How Can Personalization Offer a Solution?

GLP-1 drugs have taken the industry by storm, but real-world evidence is showing that a significant proportion of patients are discontinuing treatment courses, many attributing this to intolerable side effects. By integrating digitization and machine learning, there is an opportunity to deliver personalized care to all patients and scale precision dosing with minimal physician involvement, maximizing the effectiveness and accessibility of these drugs.

GLP-1 receptor agonist drugs, such as well-known brands Ozempic, Wegovy, Saxenda, Mounjaro and Zepbound, initially developed for Type 2 diabetes are game changers, greatly impacting traditional approaches to weight loss. Since the 2021 FDA approval of once-weekly injectable GLP-1 semaglutide (Wegovy) for weight management, the number of new users surged from 5,717 in 2020 to 120,763 in 2023, an increase of over 2,000%. As a result of this unexpected increase in demand, ongoing drug shortages hinder drug accessibility for patients currently using or wishing to use these medications for diabetes, or weight loss – highlighting the need for implementing new strategies to mitigate disruptions to patient care.  

Adherence to GLP-1 programs in clinical trials vs the real-world

While clinical studies using GLP-1s for the treatment of obesity report high one-year persistence rates of over 85%, real-word data shows a completely different story. Clinical trials overlook an individual’s unique pharmacokinetic and pharmacodynamic profile. A recent study found that during the first year of GLP-1 therapy for weight loss, only one third of patients took the medication persistently, and only 27% were adherent. This one-year persistence rate is substantially lower than the rates reported in many high-quality clinical trials and even real-world diabetes treatment studies, which show around 50% persistence.  Indeed side effect management is one of the key areas of physician issues when prescribing these drugs. This discrepancy highlights a critical flaw in the one-size-fits-all approach to medicine, which frequently results in suboptimal effectiveness and safety outcomes. 

To achieve significant health benefits and meaningful levels of weight-loss, patients are advised to adhere to at least 12 weeks of continuous treatment with GLP-1s. As with maintenance for any effective weight management strategy, long-term use of GLP-1s still requires a commitment to healthy eating and strength training to mitigate muscle loss and metabolic rate reduction. Patients that have lost 5% or more of their body weight with GLP-1 treatment have demonstrated noticeable health benefits when it comes to improving obesity-related health conditions, such as diabetes, hypertension, heart disease, liver disease, joint issues, and sleep apnea. For instance, the SELECT study, a three-year randomized clinical trial (RCT) which also used semaglutide to treat patients with obesity and pre-existing cardiovascular disease, but without diabetes, demonstrated a 20% reduction in the risk of heart attacks and strokes. Other studies have also explored the potential of GLP-1s in reducing incidents of dementia in patients with diabetes, and even treating addictive disorders.  

Increasing reports of side effects

Understanding the factors behind the significant drop in persistence and adherence rates in real-world settings is crucial, not only for patients and healthcare professionals, but to provide insight to the future of the GLP-1 market. Among factors such as affordability and accessibility, widespread reports of dose-related side effects stand out. Gastrointestinal issues, including nausea, vomiting, and diarrhea, which are particularly common during the dose escalation stage, can be severe enough for patients to take it upon themselves to discontinue treatment. 

As a result, the initial frenzy surrounding GLP-1s is giving way to growing concerns over side effects and how these drugs actually perform in the long-term. This issue was extensively discussed at the recent American Diabetes Association (ADA) 84^th Scientific Sessions, whereby clinicians shared their own experiences of prescribing this new drug category and the direct feedback from patients. Typically, GLP-1, such as semaglutide, is injected once a week, on the same day each week. Following official guidance, patients will start with a low dose (0.25 mg), which is increased every four weeks until reaching the target maintenance dose (2.4 mg). However, it was interesting to hear, in the real world, that this dose escalation schedule is not always applied or effective for all patients. For many clinicians, they are having to make additional manual medication adjustments to effectively manage side effects and maximize treatment success —including slowing dose escalation, extending use of the lowest therapeutic dose for maintenance, and microdosing/intermediate dosing. This customized dosing approach is also a main topic of discussion for patients across popular social media forums, with thousands seeking advice on how to best manage debilitating side effects without having to stop treatment altogether –  ‘Ozempic’ being the second largest thread on Reddit currently. 

This situation underscores the urgent need for patient-centric approach to treatment. People are not one-size-fits-all, so why is medicine? We need healthcare solutions that are tailored to our individual requirements, as current treatment guidelines lead to inconsistent effectiveness, and increases in safety concerns, along with avoidable healthcare costs arising from drug mismanagement and wastage. 

Tech solutions to optimize treatment and deliver personalized dosing

Advances in technology and data acquisition are driving broader accessibility to personalized care, offering innovative digital healthcare solutions that integrate therapeutic interventions with real-time monitoring devices. This transformative approach can optimize medication effectiveness and democratize higher-quality patient experiences, whilst offering support to healthcare providers. 

Looking to more established pharmaceutical areas, digitization is already making an impact, the learnings of which can be applied to explore the full potential of emerging markets like GLP-1s. For example, applying a drug-plus-software platform to achieve optimized dosing of a first-line anti-hypertensive has demonstrated improved health outcomes and medication adherence. In the study, published in Journal of American Heart Association, real-time data recorded by participants into a dedicated smartphone app was transmitted securely to a clinician, enabling personalized adjustments that ultimately resulted in significant reductions in blood pressure and fewer side effects, even in patients who were previously intolerant of standard doses. These findings highlight the potential of personalized dosing and showcase how digital tools can work with existing and new drugs to optimize patient outcomes and streamline clinician involvement, addressing one of the biggest hurdles in modern medicine – the lack of healthcare professionals.  

There is a clear and unique opportunity to apply dose optimization to GLP-1s to improve real-world persistence and adherence, supporting patients to continue treatment long enough to experience the full benefits, such as positive cardiovascular outcomes. We know clinicians are seeing the need for this and are already making necessary interventions, but struggling still to find a scalable solution. Pairing drugs with proven digital solutions, within a single label, can facilitate personalization across the GLP-1 market, improving the effectiveness of these drugs and diminishing side effects. Not only can pharma leverage this approach to deliver best-in-class clinical and commercial outcomes, it also promises to revolutionize disease management, enhancing patient safety and outcomes by tailoring treatment to individual needs, truly bringing precision care to all.

Photo: MF3d, Getty Images

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