Beyond T2D Metrics: Reframing the Conversation on Obesity

There’s a riddle about a man who weighs 148 lbs, and needs to cross a suspension bridge over a canyon that only supports 150 lbs. What’s the problem? The guy is also transporting three, 1-lb cannonballs, and he only has time for one trip across the bridge. The solution? He crosses the bridge while juggling the cannonballs.

Managing the intersection between T2D and obesity in the same patient requires some juggling. Of course, many FDA-approved drugs for T2D also address obesity. But when clinicians have a laser focus on T2D, they may fail to prioritize weight management as an integral part of T2D treatment despite clinical recommendations.

And while a patient may be ready and willing to pop a pill or even take a routine jab, asking them to maintain a healthy lifestyle may be a bridge too far.

"The recent decades have seen dramatic changes in the nutritional and eating patterns worldwide," explained Nasser Al-Salmi, RN, CNS, PhD candidate at the University of Colorado Anschutz in Aurora, Colorado, and co-authors in a 2022 Oman Medical Journal article. "Combined with increasing sedentary behavior, a worldwide epidemic of ’diabesity’ has arisen, where obesity and [T2D] occur in the same individual."

They noted that "medication adherence requires very few well-defined and brief actions daily, while the physiological, emotional, and sociological challenges associated with diet adherence may exert their amorphous and complex influences throughout the day," adding that "shifting to a healthy diet often means dropping decades of acquired eating habits and the many related small behaviors in the course of each day."

So once the appropriate medication has been prescribed, what tools are available to help clinicians aid their patients in crossing that diabesity overpasss to better health?

Tried in Trials

Several glucagon-like peptide-1 (GLP-1) receptor agonists (RA) are available to clinicians and their patients, and clinical trials have shown the "superiority of GLP-1 RA to other antihyperglycemic drugs in improving glycemic efficacy, reducing weight and blood pressure, and having a cardioprotective effect, all without the risk of hypoglycemia. These drugs have transformed the guidelines for the management of patients with diabetes," noted Katerina J. Lambrinos, PharmD, of the University of Florida College of Pharmacy in Gainesville, and co-authors in a 2023 StatPearls article.

Currently, FDA-approved treatments for the management of overweight/obesity in patients with T2D include the GLP-1 RAs semaglutide and liraglutide, and the dual GLP-1 RA/glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide. Semaglutide and liraglutide are both approved for adults with T2D as an adjunct to diet and exercise for glycemic control (in adults only for semaglutide, and in patients 10 years of age and older for liraglutide) and to reduce the risk of major cardiovascular (CV) events in adult patients with established CV disease (CVD). In addition, as of 2023, both agents have formulations approved for chronic weight management, in combination with a reduced-calorie diet and increased physical activity.

Similarly, the GLP-1RA/GIP agonist tirzepatide was initially approved in 2022 as an add-on to diet and exercise to improve glycemic control in patients with T2D, and it was later approved in 2023 as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of 30 kg/m² or greater, or 27 kg/m² or greater in the presence of at least one weight-related comorbid condition, such as T2D, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease.

One of the trials that backed tirzepatide’s FDA approval, the phase III SURMOUNT-2 trial, showed that the agent led to a mean weight loss of 12.8% and 14.7%, respectively, at doses of 10 and 15 mg in adults with T2D and a BMI ≥27 kg/m². More participants met body-weight reduction thresholds of ≥5%. Most frequent adverse events (AEs) were mild-to-moderate gastrointestinal (GI) events.

Additional agents in development for overweight/obesity in T2D patients include retatrutide, a GLP-1/GIP/glucagon receptor tri-agonist; oral orforglipron, a GLP-1 RA; and bimagrumab, an antibody that blocks activin type II receptors and stimulates skeletal muscle growth. Thus far, these agents have proven their worth in managing obesity in clinical trial settings:

• Retatrutide: A 2023 phase II trial resulted in a mean weight reduction of 24.2% after 48 weeks. Again, mild-to-moderate GI AEs were common but were "partially mitigated" by dropping the starting dose to 2 mg from 4 mg, investigators explained in The New England Journal of Medicine (NEJM). The phase III TRIUMPH-3 (BMI ≥35 kg/m² required) is currently recruiting.
• Orforglipron: A 2023 phase II trial did not include patients with T2D, but the agent was tied to a mean change from baseline in body weight that ranged from -8.6% to -12.6% across the various doses.
• Bimagrumab: In a phase II trial, patients with T2D and obesity saw metabolic improvements during 48 weeks along with positive changes in body fat mass and waist circumference. The agent is in the midst of a phase II trial that pairs it with semaglutide in overweight/obesity.

Of course, patients will only see the benefits of these agents if they stay on treatment. In all the trials, treatment adherence was good, with <5% discontinuation rate because of AEs in SURMOUNT-2. In the retatrutride trial, AE-related discontinuation did happen in up to 16% of study-drug patients, but a high percentage of patients saw the added benefit of getting off anti-hypertension (HTN) meds at 48 weeks.

For orforglipron, up to 17% of patients in the dose-groups quit the drug mostly because of GI AEs. The investigators noted in NEJM that "there is an unmet need for an oral, incretin-based therapy with efficacy similar to that of injectable GLP-1 receptor agonists. Such therapy has the potential to increase acceptance of treatment, adherence to treatment, ease of use, and persistent use."

Lastly, the bimagrumab trial saw a high completion rate of 77%, besting "many randomized clinical trials using pharmacotherapy for treating obesity, in which, on average, up to one-half of participants discontinue participation by 1 year," according to the investigators.

Getting the Most from Guidelines

Once patients are on the right meds, how can clinical guidance be used to get them on the right track for a healthier lifestyle? The first step is getting the buy in that pharmacotherapy will only take people part way across the bridge; weight management is a must to complete the journey.

In 2022, the American Association of Clinical Endocrinology (AACE) released a clinical practice guideline for comprehensive T2D care. Lawrence Blonde, MD, of Ochsner Health in New Orleans, and co-authors emphasized that the "importance of weight management throughout the natural history of [T2D] has been stressed" throughout the guidance in Endocrine Practice.

Some of the key points from AACE include:

• Most people with T2D are overweight or obese and have multiple other risk factors for the disease. Rendering the appropriate screening per 2021 U.S. Preventive Services Task Force recommendations is an important way to start the conversation, especially in those ages 35 to 70 years.
• Lifestyle interventions are vital in all T2D patients, but particularly in those who also have hypertension. Help patients set up consults with a registered dietitian for education about an overall healthy diet (Mediterranean diet, vegetarian) weight management, reduced sodium intake, and daily physical activity and regular exercise. In some cases, patients may need to be escalated to a consultation with a mental health professional or certified diabetes care and education specialist to foster long-term behavior change.
• Obesity medications, such as the GLP-1RAs are an option along with lifestyle therapy, with an aim of 7%-10% weight loss.

Of course, AACE’s focus is T2D; obesity and heart health experts have either aligned or slightly different recommendations. The 2013 guidance from the American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOS) defines a clinically meaningful weight loss as a 5% reduction in body weight. However, the AHA/ACC/TOS also advises that weight loss needs to be broached with older adults cautiously to avoid loss of lean body mass and nutritional deficiencies.

AHA/ACC/TOS concedes that weight loss in patients with obesity stage 1 or obesity stage 2 is desirable, but advises "determining weight-loss goals in collaboration with the patient rather than according to weight-related complication," as called for by the AACE.

Also of note is that although these are the most current guidelines, they are not up to date, particularly in light of the more recent FDA approvals of the various agents currently available.

Finally, it’s important for clinicians to look past the biomarkers, metrics, and BMIs, and evaluate the whole patient. A 2023 study by Cecilie Sonne Lindberg, PhD, of Steno Diabetes Center/Aarhus University Hospital in Denmark, and co-authors, took a look at how primary care physicians (PCPs) communicated with their adults patients regarding weight-related issues. Their scoping review in Obesity Science and Practice found that the research tended to focus more on physical issues, including T2D and HTN, than psychosocial issues.

Lindberg’s group also reported that a "surprising and major finding of this study, was that only one study held information on discussion of psychosocial issues — more precisely depression…This calls for future research to also highlight the topic of psychosocial issues of patients with obesity, for example, depression, anxiety, eating disorders, quality of life, etc."

In the AHA/ACC/TOS guidance, psychosocial issues are only mentioned in the context of any discussion about surgical weight loss, while AACE does state that T2D "can often be associated with depression, disordered eating…anxiety, and other psychiatric disorders, which can impair the effectiveness of lifestyle interventions. For this reason, psychological counseling and psychiatric care may be necessary."

Trials for tirzepatide, retatrutide, orforglipron, and bimagrumab are supported by Eli Lilly.

Blonde reported relationships with, and/or support from, Merck, Corcept Therapeutics, Janssen Pharmaceuticals, Lyndra Therapeutics, Novo Nordisk, Salix Pharmaceuticals, and Sanofi. Co-authors reported relationships with, and/or support from, multiple entities.

The AHA/ACC/TOS authors reported relationships with, and/or support from, multiple entities.

Blonde L, et al "American Association of Clinical Endocrinology clinical practice guideline: Developing a diabetes mellitus comprehensive care Plan-2022 update" Endocr Pract 2022; 28: 923-1049. DOI: 10.1016/j.eprac.2022.08.002.

Jensen MD, et al "2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults" Circulation 2014: S102-S138. DOI: 10.1161/01.cir.0000437739.71477.ee.