Tirzepatide-induced Weight Loss in Overweight or Obese Midlife Adults with and without Type 2 Diabetes: A Real-world Comparative Cohort Study

ABSTRACT

Background:

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, has demonstrated robust weight loss and glycemic benefits in randomized controlled trials. However, real-world data comparing its effectiveness and tolerability in obese adults with and without type 2 diabetes (T2D) are limited. The present study aimed to evaluate the real-world short-term effectiveness and safety of tirzepatide in promoting weight loss among obese or overweight adults with and without T2D.

Methods:

This was a 12-week, prospective, observational cohort study involving 93 adults (70 individuals without diabetes and 23 individuals with T2D) receiving tirzepatide at a tertiary care center. The primary outcome was change in body weight. The secondary outcomes included changes in body mass index (BMI), waist circumference (WC), glycemic parameters (in individuals with T2D only), responder thresholds (≥5%, ≥10%, and ≥15% weight loss), and adverse events (AEs). Between-group comparisons were adjusted using multivariable regression and 1:3 propensity score matching.

Results:

Both the groups experienced significant reductions in weight, BMI, and WC (all P < 0.001). The mean weight loss was − 7.14 kg in individuals without diabetes and − 5.87 kg in individuals with T2D. Among individuals with T2D, HbA1c and fasting glucose decreased by − 1.16% and − 30.9 mg/dL, respectively. A ≥10% weight loss was achieved by 21.4% of individuals without diabetes compared with 0% of individuals with T2D (P = 0.018). Adjusted between-group differences in weight change were modest and not statistically significant after propensity matching. AEs were more common in the T2D group (78.3% vs. 50.0%, P = 0.033) and were primarily mild gastrointestinal symptoms.

Conclusion:

Tirzepatide produced meaningful weight loss in both T2D and non-T2D obese adults, with additional glycemic improvements in T2D. Individuals without diabetes were more likely to achieve ≥10% weight loss, while tolerability remained acceptable in both the groups. These real-world findings support tirzepatide’s role in individualized obesity and metabolic disease management.

INTRODUCTION

Obesity and type 2 diabetes (T2D) are closely connected metabolic disorders that together contribute substantially to cardiovascular risk, early mortality, and growing healthcare demands worldwide. Their frequent coexistence is driven by shared biological mechanisms, including insulin resistance, chronic low-grade inflammation, and dysregulation of appetite and satiety signaling, which reinforce each other over time.[1] Although lifestyle and pharmacotherapy remain the cornerstone of management, long-term maintenance of weight loss and glycemic control is challenging in routine clinical practice, highlighting the need for more effective therapeutic options with broader metabolic benefits.

Tirzepatide is a first-in-class dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, rationally engineered to exploit the complementary and synergistic actions of the two incretin pathways. By simultaneously enhancing glucose-dependent insulin secretion and suppressing appetite through central and peripheral mechanisms, tirzepatide exerts broader metabolic effects than selective GLP-1 receptor agonists. Clinical trial evidence demonstrates that this dual incretin agonism translates into superior glycaemic control and substantially greater, dose-dependent weight reduction, with weight loss predominantly driven by reductions in fat mass. These combined actions position tirzepatide as a mechanistically distinct and metabolically potent therapeutic agent for the management of type 2 diabetes and obesity.[2] The SURPASS program has shown that tirzepatide is associated with significant and dose-related glycemic glycated hemoglobin (HbA1c) reductions of 1.87%–2.59% in blood in a kind of diverse T2D populations, ranging from newly diagnosed people (SURPASS-1) to those on oral medication (SURPASS-2) or insulin therapy (SURPASS-3–5). These benefits were consistently superior to those observed with placebo, semaglutide, and basal insulin comparators, highlighting the potent dual-incretin mechanism of tirzepatide. Across SURPASS trials, additional improvements included dose-related weight reduction of 6–13 kg with 40%–69% of dose-takers achieving ≥10% weight reduction in addition marked reductions in visceral and hepatic levels of fat, up to 47% reduction in liver fat and >80% reductions in fat reaching clinically meaningful histologic thresholds suggesting its importance for inclusion of T2D patients with coexisting obesity or nonalcoholic fatty liver disease.[3,4,5,6,7]

In the SURMOUNT-1 trial in people with obesity but no diabetes, tirzepatide achieved mean weight losses of 15.0%, 19.5%, and 20.9% with 5 mg, 10 mg, and 15 mg doses for 72 weeks compared with just 3.1% with placebo (P < 0.001). Notably, 91% of participants receiving the highest dose achieved at least 5% body weight reduction, confirming tirzepatide’s efficacy beyond the diabetic population.[8] Similar patterns were observed in SURMOUNT-2, where individuals with both obesity and T2D achieved up to an 11.6-percentage-point greater weight loss than placebo, despite background oral therapy.[9] SURMOUNT-3 and SURMOUNT-4, which included intensive lifestyle support or periods of extension of therapy, had continued reductions of 19.4%–20.8% with over 89% continuing their progress until 88 weeks.[10,11] Collectively, these trials demonstrate that tirzepatide can achieve magnitudes of weight loss approaching those typically observed with metabolic surgery. Although these randomized controlled trials establish the efficacy of tirzepatide under controlled conditions, there is less information about how well it works in real-world practice, particularly in subgroups defined by diabetes status.

Routine care involves additional variables, including polypharmacy, varying degrees of insulin resistance, heterogeneity in baseline metabolic status, and differences in day-to-day tolerability, all of which may influence treatment response and adherence. Notably, individuals with T2D tend to experience less weight loss than individuals without diabetes, as observed in the SURMOUNT trials. In SURMOUNT-1 (nondiabetic), a 15-mg dose resulted in a 20.9% reduction in 72 weeks, whereas in SURMOUNT-2 (T2D), a 15-mg dose showed 15.7%.[8,9] This consistent difference suggests that it might be that diabetes itself may blunt weight loss responses (possibly for deeper metabolic impairment, treatment with insulin, or chronicity of their disease). Yet, there is still a lack of real-world comparative data to validate this observation.

In addition, gastrointestinal adverse events (AEs), which are well recognized in clinical trials, may manifest differently in real-world practice, and their frequency and burden may vary between individuals with and without diabetes. Understanding these patterns is important for optimization in patient selection, titration schedules, and supportive care.

Against this background, we planned a real-world comparative cohort study to determine the early effectiveness and safety of tirzepatide in obese adults with and without T2 diabetes mellitus. Our primary objective was to compare weight loss outcomes after 12 weeks between these two groups. The secondary endpoints were changes in body mass index (BMI), waist circumference (WC), HbA1c, fasting glucose, attainment of key weight loss targets (≥5%, ≥10%, and ≥15%), and differences in AEs. We hypothesized that tirzepatide would produce significant weight loss in both the groups, with greater weight reduction and better tolerability among individuals without diabetes. Using multivariable regression and propensity score matching (PSM), we set out to produce clinically relevant results that reflect the real-life scenario of prescribing and patient diversity. These findings may help guide individualized treatment strategies for patients with obesity and metabolic disease across the midlife spectrum.

METHODS

Study design and setting

This study was a 12-week observational, real-world cohort study at a tertiary care center. The purpose was to assess the short-term effectiveness and safety of tirzepatide in adults with overweight or obesity including analysis that was stratified by the presence or absence of T2D. Data were collected prospectively between the period of July 2025 and October 2025 and as part of routine clinical care. Ethical approval was obtained from the institutional ethics committee (approval ID: SNMC/IEC/2025/68), and all the participants gave their informed consent for the use of anonymized clinical data for research purposes.

Participants

Eligible subjects were adults 18 years of age or older with a BMI of 27 kg/m² or higher newly initiated with tirzepatide for weight reduction or glycemic control. Individuals were categorized into the T2D or non-T2D group based on physician-documented diagnosis and clinical criteria such as glucose-lowering drugs or diabetes history (high recorded levels). Participants were excluded if they had received tirzepatide or any other incretin-based therapy within the previous 3 months, were concurrently taking anti-obesity agents, such as orlistat or semaglutide, had undergone bariatric surgery, or had active malignancy or endocrine disorders known to modulate weight.

Treatment protocol

Tirzepatide was prescribed based on routine clinical judgment. Treatment was initiated with tirzepatide at a dose of 2.5 mg once weekly, followed by dose escalation in 2.5 mg increments every four weeks based on tolerability and clinical response. Tirzepatide was administered as a commercially available injectable formulation (Mounjaro). The product was manufactured by Eli Lilly and Company, Indianapolis, Indiana, United States of America, and was obtained by patients through routine pharmacy purchase.

All participants received standardized counseling regarding dietary modification and physical activity as part of routine care; however, no structured or protocol-driven dietary or exercise programs were implemented specifically for this study.

Outcome measures

The primary outcome was absolute and percentage change in body weight from baseline to week 12. The secondary outcomes were changes in BMI and WC, changes in HbA1c and fasting blood glucose in the T2D subgroup, proportion of participants achieving at least 5%, 10%, and 15% weight loss, and the incidence and type of AEs. AEs were grouped as gastrointestinal, injection-site related, and other organ systems related and graded according to their severity using the Common Terminology Criteria for Adverse Events (v5.0).

Data collection procedures

All measures of anthropometric assessment were performed at baseline and week 12 using standardized clinical procedures. Weight and height were measured with calibrated digital scales, and WC was measured at the midpoint between the lowest rib and the iliac crest. Relevant laboratory values were retrieved from electronic medical records. AEs were recorded at follow-up visits using clinician enquiry and reporting by the patient and coded according to system-based classifications.

Statistical analysis

Baseline characteristics were summarized with means and standard deviations or medians and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. Between-group comparisons were done using independent t-tests or Mann–Whitney U tests (continuous variables) and Chi-square or Fisher’s exact tests (categorical variables). To meet the purpose of accounting for baseline differences, multiple models of linear regression estimates were done to study the diabetes status in association with the percentage of weight changes at the 12 weeks that at least three factors were taken into consideration (index of age, sex, and baseline weight in BMI as index of weight) and WC measurement.

A PSM approach was also used using a 1:3 nearest neighbor algorithm with a caliper width of 0.2 and matching participants with T2D to those without T2D. Matching quality was assessed with the help of standardized mean differences, with below 0.1 indicating acceptable balance. Sensitivity analyses were strong standard error estimation, nonparametric bootstrapped confidence interval (CI) with 1000 replications, and Benjamini–Hochberg to control for multiple comparisons. All analyses were carried out on R (version 4.3.2) and Stata (version 18.0), where the statistical significance was defined as two-sided P < 0.05.

RESULTS

Participant characteristics

A total of 93 adults initiated tirzepatide treatment during the study period; 70 individuals without T2D and 23 individuals with T2D were included in the analysis. The mean age of the cohort was 46.7 ± 13.4 years; individuals with T2D were significantly younger than individuals without diabetes (42.4 ± 10.8 vs. 48.0 ± 14.0 years, P = 0.04). Baseline anthropometric features were similar between the groups, with a total mean weight of 99.9 ± 16.3 kg and a mean BMI of 35.5 ± 6.2 kg/m². WC was significantly lower in individuals with T2D (121.6 ± 9.9 cm) compared with individuals without diabetes (127.8 ± 8.4 cm; P = 0.01) [Table 1].

Table 1.

Baseline demographic and clinical characteristics by diabetes status

Characteristic	Overall (n=93)	Non-T2D (n=70)	T2D (n=23)	P
Age (years)	46.7±13.4	48.0±14.0	42.4±10.8	0.04*
Female sex, n (%)	54 (58.1)	39 (55.7)	15 (65.2)	0.46
Weight (kg)	99.9±16.3	100.7±17.5	97.6±11.5	0.36
BMI (kg/m2)	35.5±6.2	35.1±6.6	36.7±4.4	0.28
Waist circumference (cm)	126.3±9.1	127.8±8.4	121.6±9.9	0.01*

*Statistically significant at P<0.05. BMI: Body mass index, T2D: Type 2 diabetes

Within-group changes after 12 weeks

There were significant improvements in the anthropometric results for both the study groups during the 12 weeks of treatment. A reduction in weight of 7.14 ± 4.61 kg (P < 0.001) accompanied by a reduction in BMI of 2.50 ± 1.61 kg/m² and a reduction of 13.0 ± 5.0 cm in WC was observed in participants without T2D. Participants with T2D lost 5.87 ± 2.58 kg (P < 0.001) with respective reductions of 2.20 ± 0.95 kg/m² in BMI and 12.4 ± 3.7 cm in WC (all P < 0.001). Only participants with T2D showed improvements in their metabolic profile, with HbA1c dropping by 1.16% (95% CI: −1.49 to − 0.83; P < 0.001) and fasting glucose by 30.9 mg/dL (95% CI: −38.0 to − 23.9; P < 0.001) [Table 2].

Table 2.

Within-group changes from baseline to 12 weeks

Variable	Non-T2D (n=70)	T2D (n=23)
Weight (kg)	−7.14±4.61 (95% CI−8.24 to−6.04), P<0.001	−5.87±2.58 (95% CI−6.99 to−4.75), P<0.001
BMI (kg/m2)	−2.50±1.61 (95% CI−2.89 to−2.12), P<0.001	−2.20±0.95 (95% CI−2.61 to−1.79), P<0.001
Waist (cm)	−13.03±4.99 (95% CI−14.22 to−11.84), P<0.001	−12.37±3.70 (95% CI−13.97 to−10.77), P<0.001
HbA1c (%)	-	−1.16±0.76 (95% CI−1.49 to−0.83), P<0.001
Fasting glucose (mg/dL)	-	−30.9±16.3 (95% CI−38.0 to−23.9), P<0.001

BMI: Body mass index, T2D: Type 2 diabetes, CI: Confidence interval, HbA1c: Hemoglobin A1c

Between-group comparisons

After adjusting for the confounding variables of age, sex, baseline BMI, and WC, individuals with T2D showed a slightly decreased rate of percentage weight reduction compared with the people without diabetes. The adjusted mean difference was + 1.74% (95% CI: 0.01–3.47; P = 0.049) although this effect was small and was no longer statistically robust after multiple comparison correction. The group differed in BMI (adjusted difference: +0.62 kg/m²; P = 0.026) and WC again (−0.43 cm; P = 0.63), but these differences were also small and were not significant corrected [Table 3].

Table 3.

Adjusted between-group differences in anthropometric outcomes

Outcome	Adjusted mean difference (T2D vs. non-T2D)	95% CI	P
Percentage weight change	+1.74	0.01 to 3.47	0.049*
BMI change	+0.62 kg/m2	0.08 to 1.16	0.026*
Waist change	−0.43 cm	−2.17 to 1.31	0.63

*Statistically significant at P<0.05. BMI: Body mass index, T2D: Type 2 diabetes, CI: Confidence interval

Responder analysis

The clinically significant thresholds of weight loss were measured in the groups. A total of 67.1% and 65.2% of the non-T2D and T2D participants achieved at least 5% weight loss (P = 1.00). Achievement of ≥10% weight loss was significantly different with 21.4% in the non-T2D group, whereas none were observed in the T2D group (P = 0.018), with maintained significant difference after Benjamini–Hochberg adjustment. These responder patterns are illustrated in Figure 1. Attainment of ≥15% weight loss was rare and did not differ between the groups [Table 4].

Figure 1.

Responder rates for clinically significant weight loss thresholds at 12 weeks. Bars show the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss, stratified by diabetes status. At the ≥10% threshold, individuals without diabetes had a significantly higher response compared with individuals with type 2 diabetes (P = 0.018, Fisher’s exact test)

Table 4.

Responder analysis at 12 weeks

Outcome	Non-T2D (n/N, %)	T2D (n/N, %)	Risk difference (95% CI)	P
≥5% weight loss	47/70 (67.1)	15/23 (65.2)	−1.9% (−26.2 to 22.4)	1.000
≥10% weight loss	15/70 (21.4)	0/23 (0.0)	−21.4% (−33.9 to−8.9)	0.018*
≥15% weight loss	2/70 (2.9)	0/23 (0.0)	−2.9% (−9.6 to 3.9)	1.000

*Statistically significant at P<0.05. T2D: Type 2 diabetes, CI: Confidence interval

Adverse events

Overall, the rate of AEs was higher in participants with T2D (78.3% vs. 50.0% of subjects without diabetes, P = 0.033). The absolute risk difference was − 28.3% (−48.8 to − 7.7). Gastrointestinal symptoms (i.e., nausea, gastroesophageal reflux, diarrhea, and vomiting) were the most frequently reported events in both the groups; they were generally mild. A single episode of hypoglycemia occurred in the T2D group which was well managed by reducing the dose of sulfonylureas; no participants discontinued therapy due to AEs [Table 5]. All gastrointestinal AEs were well dealt with the aid of proton pump inhibitors and anti-emetics.

Table 5.

Adverse events during 12 weeks of treatment

Adverse event	Non-T2D (n=70)	T2D (n=23)	P
Any adverse event	35/70 (50.0)	18/23 (78.3)	0.033*
Nausea	17/70 (24.3)	8/23 (34.8)
GERD	10/70 (14.3)	4/23 (17.4)
Diarrhea	3/70 (4.3)	2/23 (8.7)
Vomiting	2/70 (2.9)	1/23 (4.3)
Dizziness	1/70 (1.4)	1/23 (4.3)
Hypoglycemia	0/70 (0.0)	1/23 (4.3)
Abdominal pain/discomfort	1/70 (1.4)	1/23 (4.3)
Constipation	1/70 (1.4)	0/23 (0.0)

*Statistically significant at P<0.05. Values are expressed as n/N (%). GERD: Gastroesophageal reflux disease, T2D: Type 2 diabetes

Propensity score-matched analysis

A 1:3 nearest neighbor-matched cohort (23 with T2D matched to 69 without T2D) showed sufficient balance between the studied groups in baseline variables, with standardized mean differences of < 0.1 for all the studied baseline variables. In the matched analysis, the differences in percentage of weight change between the groups became less pronounced and not statistically significant (β = +1.08%, 95% CI: −0.47 to + 2.63; P = 0.169).

Sensitivity analyses and assumption

Change score distributions were found nearly normal through visual Q-Q plot inspection and Shapiro–Wilk testing. The Wilcoxon nonparametric tests and bootstrapped 95% CIs (10,000 iterations) yielded similar results. The multivariable models found lower baseline BMI (P = 0.023) and older age (P = 0.006) as independent predictors of higher percentage weight loss, whereas diabetes status, gender, and baseline WC were not significant factors in weight change.

DISCUSSION

This real-world study provides a comparative evaluation of the short-term effectiveness and tolerability of tirzepatide in obese individuals with and without T2D. In nondiabetic individuals, the average loss was more than 7 kg, while the diabetic patients lost almost 6 kg of their weight. Interestingly, the nondiabetic group showed a much higher rate of weight loss, more than 10%, and the trend was the same in the SURMOUNT program, where non-T2D populations always showed greater weight reductions than the T2D group.[8,9] The inhibition of weight loss in the presence of T2D may be due to the prevailing insulin resistance, which is a major contributor in metabolic disorders, the body losing the ability to respond to incretin hormones, and the treatment of patients with drugs that cause weight gain – insulin or sulfonylureas – being the most common ones.[2,3,6,9] These conditions, among others, may prevent the complete therapeutic effect of tirzepatide from manifesting, even in cases where the patient is on the same dosage and has the same adherence to the drug. The difference in response remained even after considering baseline anthropometric measures and was further substantiated in the responder analysis, which revealed that no participant with T2D was able to attain the ≥10% weight loss threshold. On the other hand, patients with T2D who still had insulin coming in the body were able to achieve very high glycemic control, with HbA1c dropping more than 1% and fasting glucose going down by 31 mg/dL on average during the 12-week period. These results are consistent with the early glycemic responses observed in the SURPASS trials and even more so with tirzepatide’s double push in metabolism.[3,4,5,6,7] Tirzepatide was accepted in general by the patients. The adverse effects reported in both the groups were mostly related to the gastrointestinal system.

Given the mean age of 46.7 years, our cohort represents a predominantly midlife population in whom metabolic health has important implications for long-term cardiovascular risk, functional status, and healthy ageing. In women, this period often coincides with the perimenopausal and menopausal transition, during which weight gain, central adiposity, and insulin resistance tend to accelerate. The observed effectiveness of tirzepatide in producing meaningful weight loss in this age group highlights its potential role not only in obesity management but also in midlife preventive strategies aimed at reducing future cardiometabolic burden.

The clinical trial observations revealed that the events mainly belonged to mild type and were self-limiting, and also no patient discontinuations due to such events happened. The higher AE incidence in patients with T2D might be indicative of underlying physiological weakness or the burden of concurrent medication, thus pointing out the need for and the significance of anticipatory guidance and supportive management during dose escalation. We have not only reinforced but also extended previous clinical and real-world evidence supporting tirzepatide’s effectiveness in weight and metabolic management. One meta-analysis that included nondiabetic subjects reported a mean weight loss of 13.95 kg and a total body weight decrease of 16.3% during randomized trials and a higher likelihood of gastrointestinal side effects.[12] A similar situation was with Angelopoulos et al., who reported that low-dose tirzepatide showed significant improvement in lipid profiles, HbA1c, and the hepatic steatosis index among obese nondiabetic adults over 12 weeks, with many benefits being independent of weight loss.[13] In a study done on a big real-world cohort from the UAE, Buckley et al. noted considerable increments in HbA1c (mean: −0.6%) and body weight (mean: −4.5 kg) after 40 weeks, with even more significant reductions among GLP-1 receptor agonist (RA)-naïve individuals and those with previous metabolic surgery, and they also reported a low discontinuation rate of 7.8% which was mainly due to gastrointestinal intolerance.[14] Giving more strength to these trends, a 6-month observational study from India performed by Chawla et al. (2025)[15] has shown that among T2D patients treated with tirzepatide, there have been remarkable improvements in BMI (−10.9), HbA1c (−1.48%), and WC (−8.15 cm), together with metabolic improvement being dose-dependent correlating to treatment intensity.

A positive relationship was noticed between the variations in HbA1c and BMI, which indicates a simultaneous improvement in the glycemic and anthropometric measures.[15] In summary, these outcomes point to the broad metabolic potential of tirzepatide in different populations, not just limited to weight loss. The study is characterized by a number of strengths among which are the real-world prospective design, clinically relevant outcomes, and the inclusion of a cohort which is directly comparable. Analytical rigor was further strengthened by multivariable adjustment and PSM, and the short 12-week treatment window also played a great role in the minimization of the influence of long-term behavioral variation or adherence drift. Nevertheless, the study had limitations that were important to mention. Only the early phase of response to tirzepatide was captured by the 12-week follow-up, which consequently cannot be assumed that it would be the same for long-term durability or safety. Dietary and physical activity habits were not subject to formal monitoring although standardized lifestyle counseling was part of the treatment. Moreover, the relatively small sample size – especially in the T2D subgroup – might restrict generalizability, although the main findings remained strong across sensitivity analyses.

CONCLUSION

Tirzepatide showed considerable short-term weight loss in midlife adults with and without T2D, with additional glycemic benefits in those with T2D and higher rates of ≥10% weight loss among individuals without diabetes. This real-world evidence highlights tirzepatide’s importance in the personalized treatment of obesity and metabolic diseases.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.