Early Dose Escalation of Tirzepatide after Switching from Semaglutide in Type 2 Diabetes Mellitus

Abstract

Tirzepatide has demonstrated greater efficacy than semaglutide in improving glycemic control and reducing body weight in patients with type 2 diabetes mellitus (T2DM). However, the optimal tirzepatide dose following a switch from 1.0 mg of semaglutide remains unclear. This retrospective study included 15 T2DM patients who switched to tirzepatide due to inadequate weight loss. All patients started tirzepatide at 2.5 mg, with escalation to either 7.5 mg (n=10) or 10 mg (n=5). Changes in glycated hemoglobin (HbA1c) and body weight were assessed over a 3-month period. The 10 mg group experienced a significant reduction in HbA1c (−0.7%±0.3%, P<0.01) and a non-significant trend toward weight loss (−6.6±5.4 kg, P=0.07). In contrast, no significant changes were observed in the 7.5 mg group. There were no statistically significant differences between groups. Since 10 mg of tirzepatide significantly improved glycemic control after switching from 1.0 mg of semaglutide, early escalation to 10 mg may be beneficial for patients who respond inadequately to semaglutide.

GRAPHICAL ABSTRACT

INTRODUCTION

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes mellitus (T2DM) due to their dual effects on glycemic control and body weight. Among these agents, tirzepatide has shown particularly strong weight-reducing properties [1]. In clinical practice, switching from semaglutide to tirzepatide has become increasingly common, especially in patients with suboptimal weight loss, highlighting the need for optimal dosing strategies. Tirzepatide is typically initiated at 2.5 mg and titrated stepwise to higher doses depending on tolerability. However, the most appropriate dose for patients transitioning from high-dose semaglutide (1.0 mg) remains uncertain. This study aimed to evaluate the effects of different tirzepatide doses (7.5 mg vs. 10 mg) on weight reduction in patients who switched from 1.0 mg of semaglutide.

METHODS

This retrospective observational study included patients with T2DM who were switched from 1.0 mg of semaglutide to tirzepatide at our institution between April 2023 and November 2024. Sex was determined using the biological information recorded in patient medical charts. Eligible patients received a stable dose of tirzepatide for at least 3 months and had available data for body weight and glycated hemoglobin (HbA1c) both before and after treatment. No changes were made to other antidiabetic medications or lifestyle interventions during the observation period. Patients were classified into two groups based on their maintenance dose of tirzepatide: 7.5 or 10 mg. Semaglutide (Ozempic, Novo Nordisk, Bagsværd, Denmark) and tirzepatide (Mounjaro, Eli Lilly and Company, Indianapolis, IN, USA) were used. Switching to tirzepatide was considered for patients with insufficient weight loss (<3% from baseline) after several months of semaglutide therapy. The definition of insufficient response (<3% weight reduction) was based on previous studies that used this threshold to identify nonresponders to dietor lifestyle-based weight management interventions [2,3]. Tirzepatide was started at 2.5 mg once weekly and escalated following the standard 4-week titration schedule. Patients in the 7.5 mg group received 2.5 mg for the initial 4 weeks, followed by 5.0 mg for the next 4 weeks. Those in the 10 mg group underwent a 12-week escalation: 2.5 mg for 4 weeks, 5.0 mg for 4 weeks, then 7.5 mg for 4 weeks before reaching the final 10 mg dose. In patients who remained on tirzepatide 7.5 mg, escalation to 10 mg was not pursued based on clinical judgment, considering factors such as previous response and patient preference during routine care. All patients were deemed to have received an adequate trial of semaglutide. The primary endpoints were changes in body weight (ΔBW) and HbA1c (ΔHbA1c) from baseline to 3 months. Continuous variables are presented as mean±standard deviation. Within-group comparisons were conducted using the paired t test, while between-group comparisons used unpaired t tests. Statistical significance was defined as a two-tailed P<0.05. Analyses were performed with SPSS version 23.0 (IBM Corp., Armonk, NY, USA). Written informed consent by the patients was waived due to a retrospective nature of our study. The study was approved by the institutional ethics committee of Jinnouchi Hospital (approval number: 2024-12-3) and conducted in accordance with the Declaration of Helsinki. The study was registered in the UMIN clinical trials registry (ID: UMIN000057510).

RESULTS

Of the patients who switched from 1.0 mg of semaglutide to tirzepatide, 10 received a maintenance dose of 7.5 mg and five received 10 mg; all maintained their respective doses for at least 3 months. No gastrointestinal adverse events were reported during tirzepatide dose escalation or maintenance, and no patient discontinued therapy due to tolerability issues. In the 7.5 mg group (n=10), the mean age was 55.3±7.7 years, with 60.0% male; mean HbA1c was 6.4%±1.3% (46±14 mmol/mol), and mean body mass index (BMI) was 30.4±4.9 kg/m². In the 10 mg group (n=5), the mean age was 58.6±9.0 years, 80.0% were male, mean HbA1c was 6.6%±1.0% (49±11 mmol/mol), and BMI was 31.9±2.5 kg/m². As shown in Fig. 1, both groups exhibited decreases in HbA1c and body weight, but a significant reduction in HbA1c was observed only in the 10 mg group. Baseline characteristics of study participants are presented in Table 1. In the 7.5 mg group, there were no significant improvements in glycemic control (HbA1c: 6.4%±1.3% to 6.2%±1.6%; P=0.47; ΔHbA1c: −0.2%±0.8%) or body weight (85.3±17.1 kg to 82.7±17.0 kg; P=0.07; ΔBW: −2.6±4.0 kg). In contrast, the 10 mg group demonstrated a significant improvement in glycemic control (6.6%±1.0% to 5.9%±0.8%, P<0.01; ΔHbA1c: −0.7%±0.3%), while the reduction in body weight (91.4±11.1 kg to 85.4±11.6 kg, P=0.07; ΔBW: −6.6±5.4 kg) did not reach statistical significance. However, between-group comparisons of changes in HbA1c and body weight were not statistically significant (ΔHbA1c: −0.2% vs. −0.7%, P=0.24; ΔBW: −2.6 kg vs. −6.6 kg, P=0.19).

Fig. 1.

Changes in glycated hemoglobin (HbA1c) (A) and body weight (B) from baseline to 3 months after switching from 1.0 mg of semaglutide to tirzepatide. Patients were grouped according to the final dose of tirzepatide (7.5 mg [n=10] or 10 mg [n=5]). Bars represent mean values. Given the small sample size, error bars were intentionally omitted to minimize the risk of misrepresenting variability and to avoid potentially misleading visual interpretation of standard deviations. P values reflect within-group comparisons using the paired t test. ΔHbA1c and Δbody weight are shown below each bar.

Table 1.

Baseline characteristics of the study participants

Characteristic	7.5 mg group (n=10)	10 mg group (n=5)
Age, yr	55.3±7.7	58.6±9.0
Male sex, %	60.0	80.0
HbA1c, %	6.4±1.3	6.6±1.0
Height, cm	166.9±7.9	168.9±5.2
BW, kg	85.3±17.1	91.4±11.1
BMI, kg/m2	30.4±4.9	31.9±2.5

Values are expressed as mean±standard deviation. Within-group comparisons were performed using the paired t test; between-group comparisons using the unpaired t test.

HbA1c, glycated hemoglobin; BW, body weight; BMI, body mass index.

DISCUSSION

In this study, 7.5 mg of tirzepatide did not produce significant improvements in glycemic control or body weight after switching from 1.0 mg of semaglutide, while the 10 mg dose resulted in significant HbA1c reduction, but not significant weight loss. These results suggest that early escalation to 10 mg or higher may benefit patients who have responded inadequately to semaglutide. Although between-group differences were not statistically significant, the 10 mg group exhibited clinically meaningful improvements in HbA1c and a greater trend toward weight loss. This finding may indicate the benefits of more intensive dosing in selected patients and is consistent with previous reports of dose-dependent tirzepatide efficacy.

Tirzepatide is a dual GLP-1RA and glucose-dependent insulinotropic polypeptide receptor agonist, exerting synergistic effects on insulin secretion and weight reduction [4], and offering enhanced efficacy compared to semaglutide. In the A Study of Tirzepatide [LY3298176] in Participants with Type 2 Diabetes (SURPASS-2) trial, tirzepatide (5 to 15 mg) was superior to 1.0 mg of semaglutide in improving both HbA1c and body weight [5], in contrast to our results. However, the SURPASS J-mono trial found that although HbA1c reductions increased with higher tirzepatide doses, differences in weight loss between 10 and 15 mg were modest, which is consistent with our observations [6]. Additionally, a recent real-world study reported greater weight loss with tirzepatide than with semaglutide in overweight or obese patients [7], which further supports the trends noted in our study.

Importantly, no gastrointestinal adverse events were observed during tirzepatide therapy in this cohort. This may be attributed to the fact that all patients had previously tolerated 1.0 mg of semaglutide, suggesting a population with high baseline tolerability to incretin-based treatments.

This study has several limitations, including a small sample size and a short observation period, which may limit statistical power. The single-center, retrospective design may also introduce selection bias. Larger, prospective studies will be necessary to confirm these findings.