Real-World Weight Loss With Injectable Semaglutide vs Dulaglutide for Diabetes

ABSTRACT

Objective: To compare the real-world effects of weekly injectable semaglutide (Ozempic) vs dulaglutide (Trulicity) on weight loss in an urban, predominantly African American patient sample with type 2 diabetes (T2D).

Study Design: This retrospective cohort study included adult patients with T2D at an academic internal medicine clinic who were initiated on semaglutide or dulaglutide.

Methods: The primary outcome was the percentage change in actual body weight (ABW) from baseline at 52 weeks. Secondary outcomes included mean weight loss in kg, weight loss of at least 5% and at least 10% at 52 weeks, percentage change in hemoglobin A_1c (HbA_1c) at 52 weeks, and HbA_1c levels of less than 7% and less than 8% at 52 weeks.

Results: The percentage change in ABW from baseline at 52 weeks was greater with semaglutide (n = 60) than with dulaglutide (n = 60) (–6.51% vs –1.14%; P = .001). The absolute change in ABW at 52 weeks was greater with semaglutide than with dulaglutide (–15.98 kg vs –4.93 kg; P = .001). More patients using semaglutide achieved weight loss of at least 5% and at least 10% at 52 weeks than those using dulaglutide (≥ 5%: 51.7% vs 25.0%; P = .003; ≥ 10%: 31.7% vs 8.3%; P = .001). A higher percentage of patients using semaglutide than those using dulaglutide achieved an HbA_1c less than 7% and less than 8% at 52 weeks (< 7%: 53.3% vs 38.3%; P = .100; < 8%: 78.3% vs 68.3%; P = .220). The absolute change in HbA_1c was greater with semaglutide than dulaglutide (–2.15% vs –1.36%; P = .033).

Conclusions: Treatment with semaglutide resulted in a greater reduction in body weight and HbA_1c than with dulaglutide in a real-world study of patients with T2D.

Am J Manag Care. 2026;32(6):In Press

Takeaway Points

In a real-world study of adult patients with type 2 diabetes (T2D) treated with semaglutide (Ozempic) or dulaglutide (Trulicity) at weekly doses up to the highest available dose, semaglutide resulted in greater reductions in body weight and hemoglobin A_1c than dulaglutide.

• The mandated lifestyle interventions and/or restricted use of other medications for T2D in some large clinical trials may result in differences in observed weight loss with semaglutide and dulaglutide between real-world patients and patients in clinical trials.
• Patients of African American race have been underrepresented in other existing studies comparing semaglutide and dulaglutide. This study adds to existing literature by including a primarily African American patient population.

Overweight and obesity are common comorbid conditions in patients with type 2 diabetes (T2D) and increase the risk of several health conditions, including T2D, hypertension, and cardiovascular disease.^1,2 In patients with T2D and overweight or obesity, weight management is recommended as a primary goal of treatment due to evidence supporting the benefits of weight loss in this patient population.³ Modest (3%-7% of body weight) or significant (> 10% of body weight) weight loss improves glycemic control and other cardiovascular risk factors, including hypertension and hyperlipidemia, in patients with T2D.^3-5

Injectable incretin analogues, including glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonists, are the preferred pharmacotherapeutic treatment for patients with T2D and overweight or obesity.³ The American Diabetes Association Standards of Care in Diabetes categorizes them based on efficacy for weight loss.⁶ Agents with a very high efficacy for weight loss include tirzepatide (Mounjaro) and semaglutide (Ozempic), and agents with a high efficacy include liraglutide (Victoza) and dulaglutide (Trulicity).⁶ Injectable semaglutide and dulaglutide are 2 commonly used incretin analogues with once-weekly dosing.⁷ These agents have been available for several years, with the FDA initially approving dulaglutide in 2014 and semaglutide in 2017.^8,9 Additional, higher weekly doses were approved in September 2020 for dulaglutide and March 2020 for semaglutide, providing the opportunity to titrate these agents for further glycemic control and/or weight loss benefit.^10,11

In the head-to-head phase 3 SUSTAIN-7 trial (NCT02648204), in which 77.4% of patients were White, injectable semaglutide was found to be superior to dulaglutide in the reduction of mean body weight.¹² However, the maximum weekly doses of semaglutide and dulaglutide in this study were 1 mg and 1.5 mg, respectively. A multilevel network meta-regression that indirectly compared the higher weekly doses of semaglutide and dulaglutide demonstrated a greater reduction in body weight with semaglutide 2 mg weekly than with dulaglutide 4.5 mg weekly, with an estimated treatment difference of –2.57 kg (95% CI, –3.90 to –1.24).¹³ A head-to-head randomized controlled trial including these higher doses has yet to be performed.

Although the existing phase 3 clinical trials comparing semaglutide and dulaglutide are large and well-designed, the lifestyle interventions mandated may increase the weight loss observed vs that observed in the real-world setting. Another limitation of the available randomized controlled trials for weight loss with injectable incretin analogues is that predominantly White patient samples are enrolled. Other races, including African American patients, are underrepresented. The purpose of this study was to compare the real-world effect of once-weekly injectable semaglutide and dulaglutide, up to the maximum allowable doses in the package inserts, on weight loss in an urban, predominantly African American patient sample with T2D.

METHODS

Study Design

This was a single-center, retrospective cohort study of adult patients with T2D initiated on semaglutide or dulaglutide between January 2021 and September 2022 at an academic internal medicine clinic. This study was approved by the health system’s institutional review board.

At the time of writing, there were 20 senior staff physicians and 118 medical residents (the latter averaging 1 clinic day per week) practicing in this clinic. In addition, there was 1 embedded clinic pharmacist practicing under a collaborative practice agreement for disease states that included T2D. Patients in this study could have been seen by a physician, a pharmacist, or both for diabetes management during the study period. There were no protocols in place mandating a set titration schedule for semaglutide or dulaglutide for physicians or the embedded clinic pharmacist.

Patients were included if they were newly prescribed semaglutide or dulaglutide between January 2021 and September 2022 and maintained an active prescription for at least 52 weeks. Patients were categorized into a dose group based on the highest dose they had a prescription for at any point during the study period. In addition, included patients had to have documentation in at least 1 outpatient note confirming the start of prescribed medication therapy. Patients were excluded if they were younger than 18 or older than 75 years, pregnant or lactating, incarcerated, prescribed any incretin analogue in the 12 months prior to study inclusion date, or switched between different incretin analogues during the study period. Patients were also excluded if they had a body mass index (BMI) less than 18.5 or did not have a recorded actual body weight (ABW) in the electronic health record (EHR) at baseline ± 3 months or at 52 weeks ± 3 months. Data were obtained from the EHR database using query acquisition software. A manual chart review of included patients was performed to obtain data points not available on the EHR query report.

Patients in the semaglutide and dulaglutide groups were matched 1:1 using the following criteria: age, biological sex, and BMI. The age categories were early adulthood (18-39 years), middle adulthood (40-64 years), and older adulthood (65-< 75 years). The biological sex categories were male and female, as reported in the EHR. The BMI categories were normal weight (18.5-24.9), overweight (25.0-29.9), class I obesity (30.0-34.9), class II obesity (35.0-39.9), and class III obesity (> 40.0).¹⁴

Outcomes

The primary outcome was the percentage change in ABW from baseline at 52 weeks. The primary outcome was analyzed in the overall study sample and separately for low and high doses of semaglutide and dulaglutide. Low dose in this study refers to the initial weekly doses approved for dulaglutide (0.75 and 1.5 mg) and semaglutide (0.25, 0.5, and 1 mg). High dose refers to the weekly doses of dulaglutide (3 and 4.5 mg) and semaglutide (2 mg) that were approved several years after the drugs’ initial approvals.

Secondary outcomes included mean weight loss in kg, weight loss of at least 5% and at least 10% at 52 weeks, percentage change in hemoglobin A_1c (HbA_1c) at 52 weeks, and achievement of HbA_1c levels less than 7% and less than 8% at 52 weeks. Medication adverse events documented in the EHR, and whether these adverse events limited dose titration, were also collected. Additional data points collected included prescription insurance plan, management by an embedded clinic pharmacist, case management involvement, participation in medical nutrition therapy, and participation in the Diabetes Care Center. To be counted for management by an embedded clinic pharmacist, at least 2 encounters with the pharmacist during the study period were required.

Statistical Analysis

The treatment difference in body weight of semaglutide compared with dulaglutide was assumed to be 3.5 kg based on data from SUSTAIN-7.¹² An enrollment of 60 patients would yield 80% power with an α of 0.05 to detect a difference between groups for the primary outcome. To account for missing variables and differences in body weight in this study sample, a target sample size of 120 was planned.

Descriptive statistics were used to summarize baseline patient demographics and all other variables as appropriate. For the continuous variables, including the primary outcome of percentage change in ABW from baseline at 52 weeks, the Student t test was used for parametric data, and the Mann-Whitney U test was used for nonparametric data. For the nominal variables, the χ² test was used. All statistical analyses were performed with SPSS Statistics 29.0.2.0 (IBM Corp).

RESULTS

A total of 120 patients were included in the study. There were 1034 unique patients identified on the EHR query report. The patients in this report were screened at random until 60 met the criteria. Matching was then performed to include an additional 60 patients.

Baseline patient demographics were similar between the semaglutide and dulaglutide groups (Table 1). The overall study sample was primarily female (55.8%) and of African American race (86.7%). Table 2 indicates the number of patients who reached a high or low dose of semaglutide and dulaglutide. A high dose was reached in 55% of patients in the semaglutide group and 60% of patients in the dulaglutide group. The patients who reached a low dose of semaglutide had a higher baseline HbA_1c than those who reached a high dose (9.74% vs 8.78%). The patients who reached a low dose of dulaglutide had a lower baseline HbA_1c than those who reached a high dose of dulaglutide (8.67% vs 9.41%). The patients who reached a low dose of semaglutide had a lower baseline BMI than those who reached a high dose of semaglutide (34.1 vs 39.6). The patients who reached a low dose of dulaglutide had a lower baseline BMI than those who reached a high dose of dulaglutide (37.6 vs 38.5).

The percentage change in ABW from baseline at 52 weeks was greater with semaglutide than with dulaglutide. When comparing only the high-dose groups of semaglutide and dulaglutide, the percentage change in ABW from baseline at 52 weeks was –6.14% vs –5%, respectively (P = .006). The percentage change in ABW from baseline at 52 weeks in the low-dose groups was –6.97% with semaglutide vs –4.47% with dulaglutide (P = .174).

The absolute change in ABW at 52 weeks was greater with semaglutide vs dulaglutide (P = .001) (Table 3). When comparing only the high-dose groups, the change in ABW was –16.9 kg with semaglutide vs –3.3 kg with dulaglutide (P = .004). The change in ABW in the low-dose groups was –14.9 kg with semaglutide vs –11.5 kg with dulaglutide (P = .257). The absolute change in HbA_1c was greater with semaglutide than dulaglutide (–2.15% vs –1.36%; P = .033). When comparing only the high-dose groups, the absolute change in HbA_1c was –1.9% with semaglutide and –1.4% with dulaglutide (P = .198). The absolute change in HbA_1c in the low-dose groups was –2.5% with semaglutide and –1.3% with dulaglutide (P = .058).

More patients using semaglutide vs dulaglutide achieved a weight loss of at least 5% and at least 10% (P = .003 and P = .001, respectively). More patients achieved an HbA_1c less than 7% and less than 8% at 52 weeks with semaglutide vs dulaglutide (P = .100 and P = .220, respectively) (Table 3).

More patients receiving dulaglutide than semaglutide had documentation of any adverse event (Table 4). However, fewer patients in the dulaglutide group compared with the semaglutide group had documentation of an adverse event that limited dose titration.

DISCUSSION

In this real-world study of an urban, predominantly African American adult patient sample with T2D, patients who received semaglutide had greater reductions in body weight and HbA_1c than those who received dulaglutide, consistent with current evidence.^10-12 To our knowledge, this is the first study to evaluate the highest available weekly doses of semaglutide and dulaglutide in a real-world setting. Another real-world study has been performed; however, it did not include the highest available weekly doses and was not designed to compare the included GLP-1 receptor agonists.¹⁵ Whereas patients of African American race have been underrepresented in other existing literature comparing semaglutide with dulaglutide, most of the patients in this study were African American.

The results of this study differed from those of the SUSTAIN-7 trial, which found a mean reduction in body weight of 6.5 kg with semaglutide 1 mg weekly vs 3.0 kg with dulaglutide 1.5 mg weekly in patients on metformin monotherapy at 40 weeks.¹² The present study, which included higher doses and had a longer duration of 52 weeks, found a greater mean reduction in body weight for both semaglutide and dulaglutide (15.98 kg and 4.93 kg, respectively). Not only did the maximum doses, study duration, and patient populations vary, but in contrast to SUSTAIN-7, this study included patients on all other antidiabetic therapy, including insulin, which could have simultaneously been adjusted and contributed to the weight loss seen in this study.

SUSTAIN-7 was the only trial to directly compare these 2 injectable agents, but it did not include high doses. Both the phase 3 SUSTAIN FORTE (NCT03989232) and phase 3 AWARD-11 (NCT03495102) trials assessed the impact of high doses on weight loss; however, they were not designed as a head-to-head comparison, nor was weight loss the primary outcome.^10,11 SUSTAIN FORTE demonstrated that semaglutide 2.0 mg resulted in a relative weight loss of 7.2% at 40 weeks. This is higher than the results of this study, where semaglutide 2.0 mg resulted in a relative weight loss of 6.14% at 52 weeks. AWARD-11 did not assess percent change in body weight but rather change in kg and resulted in –4.9 kg weight change with dulaglutide 4.5 mg and –4.0 kg with dulaglutide 3.0 mg at 52 weeks. This is higher than the results of this study, in which high-dose dulaglutide resulted in a weight change of –3.3 kg. One limitation is that we cannot directly compare the results of AWARD-11 with our results, because the decision was made to collapse both dulaglutide high doses into one group in this study. One explanation for the notably lower weight loss found in our study is that the patient populations and study durations of these trials differed. In addition, the retrospective nature of our study did not allow us to track or mandate specific lifestyle interventions.

The most common adverse events documented in this study included nausea and vomiting, diarrhea, constipation, and appetite suppression. These adverse events are consistent with the package inserts for semaglutide and dulaglutide, as well as other existing literature. Although fewer patients in the dulaglutide group reached the maximum weekly dose during the study period than in the semaglutide group, the dulaglutide group had a higher incidence of any documented adverse event. In existing literature, semaglutide has been found to have a higher incidence of gastrointestinal adverse events than dulaglutide.¹⁶ It is possible that patients at higher risk of gastrointestinal adverse events, due to preexisting conditions or past sensitivity to other medications, may have been prescribed dulaglutide over semaglutide. This may have contributed to the higher incidence of adverse events in the dulaglutide group. Additionally, the identification of adverse events and whether the adverse event limited dose titration relied upon proper documentation in the EHR, which may have impacted the findings. Adverse events reported by patients may have been more likely to be documented in the EHR if they resulted in inability to titrate the dose.

This study identified several unexpected findings regarding differences between groups receiving high and low doses of semaglutide and dulaglutide. First, patients who received a low dose of dulaglutide had a greater reduction in body weight than those who received a high dose (–11.51 kg vs –3.32 kg). In the prospective, randomized AWARD-11 trial, dulaglutide at weekly doses of 3 mg and 4.5 mg provided larger dose-related reductions in body weight and HbA_1c than dulaglutide 1.5 mg.¹⁰ In the present study, more patients in the high-dose dulaglutide group were taking some form of insulin and select antidepressants with a known adverse event of weight gain than patients in the low-dose dulaglutide group. This may have contributed to the lower weight loss reduction observed in the high-dose dulaglutide group. Additionally, this study was unable to report on lifestyle interventions patients implemented at baseline and during therapy, which may have affected their weight.¹¹

Second, patients who received a low dose of semaglutide had a greater reduction in HbA_1c than those who received a high dose. The differing observations in this retrospective study compared with those in large randomized trials may have resulted from the small sample sizes in the individual groups.¹¹ Additionally, the baseline HbA_1c was higher in the low-dose semaglutide group than in the high-dose group. In a retrospective study of patients on GLP-1 receptor agonists, change in mean HbA_1c from baseline to first check was found to be significantly associated with baseline HbA_1c.¹⁷ A greater reduction in HbA_1c was observed in patients with a higher baseline HbA_1c.¹⁷ Thus, the higher baseline HbA_1c in the low-dose semaglutide group may have contributed to the greater reduction in HbA_1c observed.

There also were confounding factors in this retrospective study that could have affected the results. Patients were permitted to be on any combination of antihyperglycemic medications, which may have been added, discontinued, or dose-adjusted during the study period, potentially impacting both body weight and HbA_1c. Dose adjustments for concomitant medications were not collected in this study. In the AWARD-11 trial, the only other antihyperglycemic medication permitted aside from dulaglutide was metformin. The only permitted antihyperglycemic medication in the SUSTAIN FORTE trial was metformin with or without a sulfonylurea.¹¹

Limitations

There are several limitations to this study. Agent selection was based on provider and patient choice, which may have been guided by a variety of factors, including patient insurance formulary, existing data demonstrating greater weight loss with semaglutide compared with dulaglutide, and patient ability to use device type. There was also no access to outpatient pharmacy dispensing records to validate patient adherence; however, documentation in at least 1 outpatient note that confirmed the start of prescribed medication therapy was required. Lastly, at the time of this study, both semaglutide and dulaglutide were affected by drug shortages. Patients may have been unable to obtain a specific dose of semaglutide or dulaglutide during the study period, leading to gaps in therapy, temporary dose reductions, or inability to titrate the medication. In practice, patients may be switched between semaglutide and dulaglutide to navigate drug shortages; however, patients who switched agents were excluded from this study.

CONCLUSIONS

Treatment with semaglutide resulted in greater reductions in body weight and HbA_1c than dulaglutide in this real-world study of patients with T2D. This study adds to the existing literature by including the highest available weekly doses of semaglutide and dulaglutide and a patient sample predominantly of African American race, which has been underrepresented in prior studies. Future studies comparing semaglutide and dulaglutide in the real-world setting would benefit from a prospective design to better control for confounding factors.

Acknowledgments

The authors would like to acknowledge David Willens, MD, MPH, and Joshua Collins, MD.

Author Affiliations: Henry Ford Health System (AS, AL, ET), Detroit, MI; Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University (AL), Detroit, MI.

Source of Funding: None.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (AL, ET); analysis and interpretation of data (AS, AL); drafting of the manuscript (AS, AL); critical revision of the manuscript for important intellectual content (AS, AL, ET); statistical analysis (AS, AL); administrative, technical, or logistic support (AL); and supervision (AL, ET).

Address Correspondence to: Alison Lobkovich, PharmD, BCACP, Wayne State University, 259 Mack Ave, Detroit, MI 48201. Email: Alison.lobkovich@wayne.edu.

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