Much has been made about the side effects of GLP-1 medications like semaglutide or tirzepatide in recent years: Unrelenting nausea, which can last for days and lead to episodes of vomiting. Severe constipation for some that can contribute to nausea or other abdominal symptoms. Diarrhea or reflux which can be a major inconvenience in daily life.
Side effects are a common reason why patients stop their GLP-1 medication, which is troubling because these medications are meant to be taken long-term to realize and maintain their benefits. Recent data published in the journal Obesity suggests that slightly more than 50% of patients discontinue semaglutide or tirzepatide within a year of starting. A recent presentation at the American Diabetes Association meeting in Chicago added that among those who stopped, 36% cited side effects as the primary reason for stopping.
It Doesn’t Have to Be This Way
Side effects are a real part of the GLP-1 medication class, just as they are with many other highly effective medications. For many years, isotretinoin has been a key treatment option for severe acne, with a side effect profile that includes mental health concerns requiring extensive discussion between patient and provider with guidance on what to look for and a plan for what to do if those side effects occur. Amiodarone has long served as an important part of the treatment algorithm for certain types of abnormal heart rhythms despite possible complications (sometimes quite serious) related to the thyroid, liver, and/or lungs. Limiting side effects and managing them when they do arise is a key part of the provision of healthcare.
For some patients, potential side effects are reasons not to use a medicine (or a class of medications) at all. But for many others, there is clear benefit that can and should be weighed against the risks, which can often be managed with expert guidance and close monitoring. This is the lens through which the GLP-1 class of medications should be viewed: because weight loss and long-term weight loss maintenance stands to improve any of a lengthy list of medical conditions and has the potential to alleviate the shame, guilt, and bias experienced by many people with obesity, the benefits of semaglutide and tirzepatide can be extraordinary. But there must be a focus on ensuring that patients tolerate the medicine first. Without that, the benefits often cannot be fully realized.
A small short-term data set just published demonstrates this clearly: slow and steady dose titration can reduce side effects without compromising on the results. To be clear, for this study of patients with type 2 diabetes, researchers in Israel tested a “flexible titration regimen” only available for use with the Ozempic pens that allow for very narrow dose adjustments by single clicks of the pen. Semaglutide in this study was started at 5 clicks, which corresponded to a dose of 0.0675mg in week 1, and increased by 5 clicks each week until reaching the 1mg dose at 74 clicks in week 16. Members of the control group also received semaglutide but reached the study’s max dose in half the time (8 weeks). In accordance with the label standard, they spent four weeks at 0.25mg and then four weeks at 0.5mg before increasing to 1mg (max dose for Ozempic is 2mg, for Wegovy it is 2.4mg). Side effects were down significantly in the flexible titration group, while improvements in A1c and BMI were similar across both sides of the study.
Experience Confirms This Approach
Though there are many patients who can move through the standard dosing titration with few or no side effects, many others encounter some speedbumps along the way. It is in these patients where it is critical to know when and how to pivot to an alternative dosing approach. Without the flexibility of the click method – which, to reiterate, is not available for the Wegovy formulation of semaglutide or either pen formulation of tirzepatide in Zepbound or Mounjaro – there are multiple options for working with patients to find an approach that best fits what they are feeling on the medication.
Where able, utilizing the vial formulation of Zepbound affords the patient an opportunity to alter the initial dosing amount in response to the feedback they are getting from their bodies. Tirzepatide, in any formulation, does seem to be slightly better tolerated than semaglutide based on clinical anecdotes, but if either semaglutide or tirzepatide is not well tolerated, switching to the other may bring a fresh start; knowing how to dose adjust from one to the other is also a key strategy here. And should a patient have type 2 diabetes which makes them eligible for the Ozempic version, the ‘clickability’ of the Ozempic pens is another avenue to deploy this flexible approach.
Moving Forward
This new study on the flexible dosing regimen may beget larger studies to assess this question in greater detail among broader study populations. One would hope that the major pharmaceutical companies might see the discontinuation rates as incentive to pursue alternative strategies for allowing these narrower dose adjustments toward improving long-term usage. We know quite clearly that when patients stop the medication, whether for side effects or any other reason, any weight they’ve lost is likely to begin to come back with other benefits also being partially or fully reversed.
We expect to see additional medications for obesity approved in the next several years. Data like this may also signal an opportunity for companies spearheading the approval of these medications to study delivery patterns which limit side effects without forgoing any of the tremendous benefits these medications can offer. In fact, this flexible approach may help more patients stay on the medications to enable them to realize these benefits.
As with so many other pursuits in medicine and in life: slow and steady ends up winning the race. Now, we hope the pharmaceutical and research apparatuses can move quickly to give providers even more strategies for improving long-term tolerance of these important medications.
