Efficacy and safety of tirzepatide for weight loss in patients with obesity or type 2 diabetes: a systematic review and meta-analysis

Following the PRISMA guidelines, this meta-analysis was systematically conducted. RCTs investigating tirzepatide’s effectiveness and safety in patients with T2DM or obesity were considered for inclusion. Studies were eligible if they (1) compared tirzepatide to placebo, (2) reported at least one efficacy outcome (e.g., change in glycated hemoglobin [HbA1c] levels or body weight) or one safety outcome (e.g., incidence of adverse events), (3) had a follow-up duration of at least 8 weeks, and (4) were published in peer-reviewed journals. Non-human studies, trials involving pediatric participants, and non-randomized designs were not included.

Relevant studies were systematically searched in PubMed, Embase, Cochrane CENTRAL and Web of Science from inception to March 1st, 2025. The search methodology combined MeSH terms and specific keywords associated with ‘tirzepatide,’ ‘diabetes mellitus,’ ‘obesity,’ ‘randomized controlled trial,’ ‘efficacy,’ and ‘safety.’ Additionally, relevant articles were manually retrieved from reference lists and conference proceedings, with no restrictions on language.

Titles and abstracts were screened independently by two reviewers, with full-text assessments conducted for eligible studies. Conflicts were addressed through discussion or adjudication by a third reviewer. Data extraction followed a standardized template, collecting information on study characteristics (authorship, publication year, sample size, design and study duration), population characteristics (age, sex, baseline HbA1c, BMI), intervention details (tirzepatide dosage, comparator, treatment duration), primary and secondary outcomes, and safety data. In cases of missing information, the corresponding authors were approached for clarification.

To evaluate study quality, the Cochrane risk of bias tool was applied, assessing seven methodological domains: randomization, allocation concealment, participant and personnel blinding, blinding of outcome assessment, handling of missing data, selective reporting, and other biases. Each domain was categorized as having a low, high, or unclear risk of bias.

Meta-analysis was carried out using Review Manager (RevMan), applying a random-effects model to address between-study heterogeneity. Weighted mean differences (WMD) with 95% confidence intervals (CI) were used to analyze continuous outcomes, such as body weight changes and body weight loss, while odds ratios (OR) with 95% CI were utilized for dichotomous outcomes, including adverse events. Study heterogeneity was quantified using the I² statistic, with thresholds of > 50% and P <0.05 representing heterogeneity. Funnel plots were examined for potential publication bias, and subgroup analyses were performed based on baseline tirzepatide dose.

As shown in Figure 1, a comprehensive search yielded 578 records from databases (n=578) and other sources (n=1). After removing duplicates, 358 unique records were screened. A total of 360 records were excluded based on title and abstract evaluation due to irrelevance or failure to meet the eligibility criteria. Of the 38 full-text articles assessed, 27 were excluded due to reasons such as incomplete data or unsuitable study design. Finally, eleven studies met inclusion criteria and were incorporated into qualitative synthesis and meta-analysis, ensuring a rigorous and relevant data selection process.

The study characteristics were summarized in Table 1. Our meta-analysis included ten studies assessing the effects of tirzepatide on body weight reduction. The studies were conducted across various geographical locations, including multi-country trials, as well as country-specific studies from China, Japan, Germany, and the United States. The included trials were published in high-impact journals, indicating the robustness of the evidence base. The studies encompassed phase 1 to phase 3 clinical trials, with therapy durations ranging from 8 to 176 weeks. Across all trials, participants received either tirzepatide (5, 10, or 15 mg) or a placebo. Participants’ age ranged from 34.7 to 62 years, with varying proportions of male participants (ranging from 32.2% to 100%). Baseline characteristics indicated that participants generally had a BMI range of 22.6 to 38.2 kg/m² and a body weight between 63.0 and 105.8 kg, depending on the study population and inclusion criteria. Most studies included patients with elevated HbA1c levels (ranging from 5.6% to 8.5%), reflecting populations with type 2 diabetes or obesity-related metabolic conditions. Overall, the included studies represent a diverse range of patient populations, trial designs, and geographical regions, providing a comprehensive evaluation of tirzepatide’s effects on body weight reduction across different doses and treatment durations.

Risk of bias assessment, as illustrated in Figures 2A, B, was conducted across multiple domains. The overall assessment revealed that while most studies exhibited a low risk of bias, certain methodological limitations were identified. Selection bias was generally well controlled, with a majority of studies implementing appropriate random sequence generation and allocation concealment. However, some studies did not report sufficient details on their randomization process leading to an unclear risk of bias. Most studies appropriately handled performance, detection, attrition and reporting bias, resulting in a low risk of attrition bias. Additionally, other potential sources of bias were identified in a subset of studies but were not consistently addressed.

The changes in the body weight in different groups as summarized from all the studies included were shown in Figure 3. Tirzepatide caused the body weight loss in a dose-dependent manner.

Our meta-analysis evaluated effects of tirzepatide on body weight changes comparing with baseline. Heterogeneity was assessed using the I² statistic, which suggested heterogeneity (I²=94%, p<0.0001), providing rationale for employing random-effects model. Pooled analysis demonstrated a reduction in body weight in patients receiving tirzepatide comparing with placebo (WMD=-10.80, 95%CI:-10.80 to -9.99, p < 0.00001), indicating a substantial effect of the treatment (Figure 4).

For subgroup analysis, patients receiving tirzepatide 5 mg experienced body weight reduction comparing with placebo (WMD=-8.21, 95%CI:-9.02 to -7.40, p<0.0001, Figure 4). The 10 mg group exhibited a more pronounced effect (WMD=-10.70, 95% CI:-11.41 to -10.00, p<0.00001, Figure 4), indicating enhanced efficacy with increased dosage. The 15 mg group showed the greatest weight reduction, with a substantial and highly significant effect (WMD=-11.48, 95%CI:-12.11 to -10.85, p<0.0001, Figure 4), confirming a strong dose-response relationship.

Subgroup analyses by diabetes status mirrored this pattern: among patients with type 2 diabetes, mean weight changes were –6.17 kg (95% CI: –7.16 to –5.17, p < 0.00001) at 5 mg, –8.57 kg (95% CI: –9.41 to –7.74, p < 0.00001) at 10 mg, and –9.60 kg (95% CI: –10.32 to –8.89, p < 0.00001) at 15 mg. In non-diabetic participants, weight losses were larger: –12.10 kg (95% CI: –13.47 to –10.72, p < 0.00001) for 5 mg, –15.94 kg (95% CI: –17.25 to –14.62, p < 0.00001) for 10 mg, and –17.86 kg (95% CI: –19.19 to –16.54, p < 0.00001) for 15 mg, underscoring greater absolute weight reduction in non-diabetic cohorts (). 1

For weight loss ≥ 5%, heterogeneity was determined by I² statistic, which suggested heterogeneity (I²=82%, p<0.0001), providing rationale for employing random-effects model. Aggregated data indicated that tirzepatide treatment was correlated with higher likelihood of achieving ≥5% body weight loss comparing with placebo (OR=11.32, 95%CI:10.12 to 12.66, p<0.0001, Figure 5).

For subgroup analysis, patients receiving tirzepatide 5 mg showed increase in individuals achieving ≥5% weight loss comparing with placebo (OR=9.43, 95%CI:7.63 to 11.65, p<0.0001, Figure 5). The 10 mg group exhibited a more pronounced effect (OR=11.21, 95%CI:9.33 to 13.47, p<0.0001, Figure 5). The 15 mg group showed the greatest impact, with a substantially higher proportion of patients achieving ≥5% weight loss (OR=13.19, 95%CI:10.91 to 15.94, p<0.0001, Figure 5), confirming a strong dose-response relationship.

When stratified by diabetes status, type 2 diabetic patients exhibited ORs of 15.70 (95% CI: 9.49–25.98, p < 0.00001) at 5 mg, 12.20 (95% CI: 9.14–16.27, p < 0.00001) at 10 mg, and 15.01 (95% CI: 11.15–20.21, p < 0.00001). Among non‐diabetic participants, the corresponding ORs were 8.30 (95% CI: 6.56–10.49, p < 0.00001), 10.62 (95% CI: 8.37–13.46, p < 0.00001), and 12.13 (95% CI: 9.48–15.51, p < 0.00001) at 5, 10, and 15 mg, respectively (). 1

For weight loss ≥ 10%, heterogeneity was determined by I² statistic, which suggested heterogeneity (I² = 70%, p < 0.0001), providing rationale for employing random-effects model. Aggregated data indicated that tirzepatide treatment was correlated with a significantly higher likelihood of achieving ≥10% body weight loss comparing with placebo (OR=14.77, 95%CI:13.02 to 16.76, p<0.0001, Figure 6).

For subgroup analysis, patients receiving tirzepatide 5 mg showed increase in individuals achieving ≥10% weight loss comparing with placebo (OR=9.64, 95%CI: 7.63 to 12.20, p<0.0001, Figure 6). The 10 mg group exhibited a more pronounced effect (OR= 15.87, 95%CI:12.85 to 19.60, p<0.0001, Figure 6). The 15 mg group showed similar effects with 10 mg group, with a substantially higher proportion of patients achieving ≥10% weight loss (OR=19.31, 95%CI:15.56 to 23.95, p<0.0001, Figure 6).

For the ≥ 10% weight-loss threshold, the overall OR was 19.88 (95% CI: 14.53–27.21, p < 0.0001). In diabetic patients, ORs were 35.62 (95% CI: 10.00–126.86, p < 0.00001) at 5 mg, 21.51 (95% CI: 14.23–32.51, p < 0.00001) at 10 mg, and 25.53 (95% CI: 16.80–38.79, p < 0.00001) at 15 mg. Non-diabetic participants showed ORs of 8.61 (95% CI: 6.77–10.93, p < 0.00001), 13.88 (95% CI: 10.86–17.74, p < 0.00001), and 17.02 (95% CI: 13.24–21.88, p < 0.00001) at 5, 10, and 15 mg, respectively (). 1

For weight loss ≥ 15%, heterogeneity was determined by I² statistic, which suggested heterogeneity (I² = 56%, p = 0.002), providing rationale for employing random-effects model. Aggregated data revealed that tirzepatide treatment was correlated with a significantly higher likelihood of achieving ≥15% body weight loss comparing with placebo (OR=18.07, 95%CI:15.41 to 21.18, p<0.0001, Figure 7).

For subgroup analysis, patients receiving tirzepatide 5 mg showed increase in individuals achieving ≥15% weight loss comparing with placebo (OR=9.54, 95%CI: 7.14 to 12.73, p<0.0001, Figure 7). The 10 mg group exhibited a more pronounced effect (OR=20.77, 95%CI:15.84 to 27.23, p<0.0001, Figure 7). The 15 mg group showed the greatest impact, with a substantially higher proportion of patients achieving ≥15% weight loss (OR=26.11, 95%CI:19.86 to 34.32, p<0.0001, Figure 7), confirming a strong dose-response relationship.

Finally, for achieving ≥ 15% weight loss, the pooled OR was 23.13 (95% CI: 16.17–33.07, p < 0.0001). Diabetic patients demonstrated ORs of 20.03 (95% CI: 3.87–103.64, p < 0.00001) at 5 mg, 30.19 (95% CI: 15.33–59.44, p < 0.00001) at 10 mg, and 41.04 (95% CI: 20.76–81.11, p < 0.00001) at 15 mg. In the non-diabetic subgroup, corresponding ORs were 9.12 (95% CI: 6.80–12.23, p < 0.00001), 18.58 (95% CI: 13.86–24.90, p < 0.00001), and 22.65 (95% CI: 16.86–30.44, p < 0.00001) at 5, 10, and 15 mg, respectively (). 1

The incidence heatmap shows that gastrointestinal side effects, particularly nausea, vomiting, and dyspepsia, rise markedly with tirzepatide dose (e.g., nausea increases from ~10% on placebo to ~30% at 15 mg), while non-GI events remain low (<10%) across all arms. Serious adverse events and drug discontinuations stay below 5% for all doses, highlighting an overall favorable safety profile (Figure 8A). When normalized to placebo, decreased appetite exhibits the greatest fold-increase (~3× at 15 mg), followed by vomiting (~2.5×) and nausea (~2×), whereas non-GI effects show minimal relative change (<1.5×) (Figure 8B). Together, these heatmaps underscore that tirzepatide’s dose-dependent tolerability concerns are driven primarily by gastrointestinal adverse events.

For any adverse event, heterogeneity was determined by I² statistic, which suggested heterogeneity (I²=62%, p<0.0001), providing rationale for employing random-effects model. Aggregated data indicated that patients receiving tirzepatide had a higher likelihood of experiencing adverse effects comparing with placebo group (OR=1.34, 95%CI:1.21 to 1.47, p<0.0001,). For subgroup analysis, patients receiving tirzepatide 5 mg reported higher incidence of adverse events comparing with placebo (OR=1.48, 95%CI:1.22 to 1.80, p<0.0001,). Similar results were found in 10 and 15 mg subgroups. 1 1

Subgroup analysis by diabetic status () revealed that among diabetic patients, the 5 mg dose showed a non-significant trend toward more adverse events (OR=1.38, 95% CI 0.97–1.96, p = 0.05), whereas non-diabetic patients at 5 mg experienced a significant increase (OR=1.53, 95% CI 1.22–1.92, p = 0.0003). At 10 mg, diabetic patients had a modest yet significant increase (OR=1.19, 95% CI 0.92–1.53, p = 0.0003), while non-diabetics showed an even larger effect (OR=1.75, 95% CI 1.40–2.20, p < 0.00001). At 15 mg, both diabetic (OR 1.26, 95% CI 1.00–1.59, p < 0.00001) and non-diabetic (OR=1.05, 95% CI 0.85–1.30, p = 0.63) subgroups trended in the same direction, though statistical significance was confined to the diabetic cohort. 1

For SAEs, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.93), providing rationale for employing random-effects model. Aggregated data revealed no potentiation in risk of SAEs with tirzepatide treatment comparing with placebo (OR=0.97, 95%CI:0.83-1.14, p=0.74,), indicating that the treatment was generally well tolerated. Subgroup analysis by tirzepatide dose demonstrated that SAEs did not differ among dosing groups (). Diabetic and non-diabetic subgroups likewise showed no significant differences in SAE risk at any dose (). 1 1 1

For adverse events leading to treatment discontinuation, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²= 8%, p=0.18), providing rationale for employing fixed-effects model. Aggregated data indicated that tirzepatide group had higher likelihood of discontinuing treatment comparing with placebo (OR=1.98, 95%CI: 1.63 to 2.61, p<0.0001,). 1

For subgroup analysis, a dose-response relationship was observed, with higher tirzepatide doses associated with greater treatment discontinuation rates. The 5 mg group exhibited a lower discontinuation rate (OR=1.57, 95%CI:1.05 to 2.36, p=0.03,), while the 10 mg and 15 mg groups demonstrated a significantly higher likelihood of treatment withdrawal due to adverse events (10 mg: OR=1.93, 95%CI: 1.38 to 2.69, p=0.0001; 15 mg: OR=2.31, 95%CI:1.69 to 3.14, p<0.0001,). In diabetic patients, only the 15 mg dose significantly increased discontinuations (OR=2.17, 95% CI 1.37–3.45, p = 0.001), whereas in non-diabetics both 10 mg (OR=2.26, 95% CI 1.48–3.43, p = 0.0001) and 15 mg (OR=2.42, 95% CI 1.59–3.67, p < 0.0001) were significant (). 1 1 1

For nausea, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=70%, p<0.00001), providing rationale for employing random-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of nausea comparing with placebo (OR=3.08, 95%CI:3.74 to 3.46, p<0.0001,). For subgroup analysis, 5 mg group exhibited a higher incidence of nausea comparing with placebo (OR=2.24, 95%CI:1.78 to 2.81, p<0.0001,), while 10 and 15 mg groups demonstrated a significantly higher incidence of nausea (10 mg: OR=3.45, 95 CI:2.82 to 4.21, p<0.0001; 15 mg: OR=3.45, 95%CI:2.84 to 4.18, p<0.0001,). In diabetics, ORs ranged from 3.28 (5 mg) to 4.32 (15 mg); in non-diabetics, from 2.10 (5 mg) to 3.32 (10 mg) (). 1 1 1 1

For vomiting, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.94), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of nausea comparing with placebo (OR=5.51, 95%CI:4.40 to 6.91, p<0.0001,). For subgroup analysis, patients receiving tirzepatide 5 mg had an increase in vomiting events comparing with placebo (OR=5.06, 95%CI:3.48 to 7.36, p<0.0001,). The 10 mg group exhibited a more pronounced effect (OR=6.56, 95%CI:461 to 9.34, p<0.0001,). The 15 mg group showed the greatest impact, with a substantially higher proportion of patients experiencing vomiting (OR=6.06, 95%CI:4.16 to 8.82, p<0.0001,), confirming a strong dose-response relationship. In diabetic patients, the effect grew from OR 2.73 at 5 mg to OR 5.08 at 15 mg; non-diabetics showed an even steeper dose-response from OR 5.27 to OR 8.24 (). 1 1 1 1 1

For constipation, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.78), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of constipation comparing with placebo (OR=3.10, 95%CI:2.55 to 3.75, p<0.0001,). 1

For subgroup analysis, patients receiving tirzepatide 5 mg reported a greater incidence of constipation comparing with placebo group (OR=3.08, 95%CI:2.28 to 4.17, p<0.0001,). Similar results were observed in10 mg and 15 mg subgroups (). In diabetics, the 5 mg effect was particularly pronounced (OR 3.39), while non-diabetics had ORs from 3.05–3.30 (). 1 1 1

For abdominal pain, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.97), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of abdominal pain comparing with placebo (OR=1.85, 95%CI:1.47 to 2.34, p<0.0001;). For subgroup analysis, 5 mg group showed potential risk (OR=1.72, 95%CI:1.09 to 2.71, p=0.02,), while 10 and 15 mg groups exhibited higher likelihood of experiencing abdominal pain (10 mg: OR=1.76, 95%CI:1.18 to 2.63, p=0.006; 15 mg: OR=2.02, 95%CI: 1.40 to 2.92, p=0.0002,). Among diabetics only the 15 mg dose was significant (OR=2.97, p = 0.0005), while non-diabetics showed significant effects at 5 mg (OR=1.75) and 10 mg (OR=1.77) (). 1 1 1 1

For decreased appetite, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.78), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of decreased appetite comparing with placebo (OR=4.28, 95%CI:3.53 to 5.18, p<0.0001,). For subgroup analysis, patients receiving tirzepatide 5 mg reported a greater incidence of decreased appetite comparing with placebo group (OR=3.67, 95%CI: 2.49 to 5.42, p<0.0001,). Similar results were found in the 10 mg and 15 mg subgroups. When stratified by diabetic status, diabetic participants experienced ORs ranging from 7.10 to 7.55 across the three doses, whereas non-diabetic participants showed ORs of 2.98 to 3.81 (all p < 0.001) (). 1 1 1

For dyspepsia, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.97), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of dyspepsia comparing with placebo (OR=2.50, 95 CI:2.07 to 3.01, p<0.0001,). For subgroup analysis, patients receiving tirzepatide 5 mg reported a greater incidence of dyspepsia comparing with placebo group (OR=2.12, 95%CI:1.49 to 3.03, p<0.0001,). Similar results were observed in 10 and 15 mg subgroups. In diabetic patients, ORs ranged from 2.41 to 3.26, while non-diabetic patients had ORs between 1.94 and 2.87 (all p < 0.01) (). 1 1 1

For dizziness, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=0%, p=0.83), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had a higher incidence of dizziness comparing with placebo (OR=1.81, 95%CI:1.40 to 2.35, p<0.0001,). For the subgroup analysis, the 5 mg group showed no potential risk (OR=1.56, 95%CI:0.95 to 2.57, p=0.06,), while the 10 mg and 15 mg groups exhibited a significantly higher likelihood of experiencing abdominal pain (10 mg: OR=2.40, 95%CI:1.57 to 3.67, p<0.001; 15 mg: OR=1.49, 95%CI:0.97 to 2.30, p=0.04,). The 5 mg dose was not significantly associated with dizziness in either diabetic (OR=0.92, 95% CI: 0.13–6.82, p>0.05) or non-diabetic populations (OR=1.62, 95% CI: 0.97–2.70, p>0.05). However, a significantly increased risk was observed for the 10 mg dose, particularly in the non-diabetic group (OR=2.28, 95% CI: 1.40–3.70, p=0.0008). The 15 mg dose showed a trend toward increased risk in both subpopulations but did not reach statistical significance (). 1 1 1 1

For headache, heterogeneity was determined by I² statistic, which suggested no heterogeneity (I²=6%, p=0.52), providing rationale for employing fixed-effects model. Aggregated indicated that patients treated with tirzepatide had no risk of headache comparing with placebo (OR=1.00, 95%CI:0.84 to 1.20, p=0.97,). The subgroup analysis showed similar findings. Subgroup analysis confirmed consistent findings across all dose groups and both diabetic and non-diabetic patients (). 1 1

For hypoglycemia, heterogeneity was determined by I² statistic, which suggested heterogeneity (I²=65%, p<0.0001), providing rationale for employing random-effects model. Aggregated data indicated that patients treated with tirzepatide had no risk of hypoglycemia comparing with placebo (OR= 2.05, 95%CI:0.95 to 4.42, p=0.07,). The subgroup analysis showed similar findings. Among non-diabetic patients, a significant increase in hypoglycemia was observed with the 5 mg dose (OR=9.30, 95% CI: 1.18–73.66, p=0.03). In diabetic patients, none of the dose groups demonstrated a significant effect (). 1 1

For nasopharyngitis, heterogeneity was determined by I² statistic, which suggested heterogeneity (I²=0%, p=0.71), providing rationale for employing fixed-effects model. Aggregated data indicated that patients treated with tirzepatide had lower risk of nasopharyngitis comparing with placebo (OR=0.71, 95%CI:0.50 to 0.90, p=0.005,). For the subgroup analysis,5 and 15 mg groups showed no potential risk (5 mg: OR=0.93, 95%CI:0.59 to 1.45, p=0.74; 15 mg: OR=0.70, 95%CI: 0.47 to 1.03, p=0.07,), while the 10 mg group exhibited a significantly lower likelihood of experiencing nasopharyngitis (OR=0.58, 95%CI:0.38 to 0.88, p=0.01,). A significant reduction in the 10 mg dose group (OR=0.49, 95% CI: 0.30–0.79, p=0.004), particularly in diabetic patients. However, the 5 mg (OR=0.77, 95% CI: 0.45–1.32, p=0.35) and 15 mg groups (OR=0.73, 95% CI: 0.48–1.11, p=0.14) did not demonstrate statistically significant differences from placebo (). 1 1 1 1

Funnel plots of our meta-analysis are shown in-, and funnel plot results indicated no publication bias. 1 1

The original contributions presented in the study are included in the article/. Further inquiries can be directed to the corresponding authors. 1