Type 2 diabetes mellitus (T2DM) and obesity are interrelated chronic disorders that significantly contribute to the global burden of disease. Effective management now extends beyond glycemic control to include sustained weight reduction, as even modest weight loss has been shown to improve insulin sensitivity, cardiovascular risk factors, and overall metabolic outcomes. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide (marketed as Ozempic), have emerged as highly effective agents for achieving both substantial weight loss and improved glycemic control.

Semaglutide acts by enhancing glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety, thereby facilitating significant reductions in body weight and glycated hemoglobin levels. Large-scale clinical trials have demonstrated that semaglutide can induce weight loss exceeding 10–15% of baseline body weight, with some patients achieving remission of T2DM [1,2]. These findings have positioned GLP-1 receptor agonists as a cornerstone in the management of patients with obesity and T2DM.

Despite these benefits, an important clinical concern relates to the sustainability of treatment effects after discontinuation. Available evidence suggests that cessation of GLP-1 RA therapy is often followed by partial or substantial weight regain, accompanied by deterioration in glycemic parameters [3,4]. This has led to the perception that long-term or continuous therapy may be required to maintain metabolic benefits. However, emerging clinical observations indicate that a subset of patients particularly those achieving marked weight reduction and adhering to sustained lifestyle modifications may retain a significant proportion of these benefits even after treatment withdrawal.

Given the limited and heterogeneous data in this area, further investigation is warranted to clarify the durability of weight loss and glycemic remission following discontinuation of semaglutide. The present study was therefore designed to evaluate weight maintenance and glycemic outcomes over a six-month period after stopping semaglutide in patients who had previously achieved substantial weight loss and remission of T2DM. Understanding these outcomes may help refine long-term management strategies and identify patients who are more likely to sustain therapeutic gains without ongoing pharmacological intervention.

Study Design and Setting This prospective observational study was conducted at the Department of Endocrinology and Diabetes, South Punjab Hospital, Multan, Pakistan, over a period of 18 months from November 2024 to April 2026. The study was designed to assess weight maintenance and glycemic outcomes in patients with type 2 diabetes mellitus (T2DM) following discontinuation of semaglutide therapy. Study Population A total of 50 adult patients diagnosed with T2DM who had previously received semaglutide therapy for 12 months were enrolled through non-probability consecutive sampling. Eligible participants were those who had successfully completed one year of semaglutide treatment and achieved both clinically significant weight reduction and diabetes remission prior to discontinuation. Inclusion Criteria Patients were included if they met all of the following criteria: • Age between 18 and 60 years • Diagnosed with T2DM according to American Diabetes Association criteria • Completed 12 months of semaglutide treatment • Achieved at least 20% reduction in baseline body weight • HbA1c <6.5% without use of any glucose-lowering medications at the time of semaglutide discontinuation • Willingness to participate in six-month follow-up after treatment cessation Exclusion Criteria Patients were excluded if they had: • Type 1 diabetes mellitus • Pregnancy or lactation • History of bariatric surgery • Chronic kidney disease stage IV or higher • Active malignancy or severe systemic illness • Use of other anti-obesity medications during follow-up • Incomplete clinical records or loss to follow-up Study Procedure Baseline demographic and clinical data were recorded at the time of semaglutide discontinuation, including age, sex, duration of diabetes, body weight, body mass index (BMI), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c). Following discontinuation of semaglutide, all patients were advised to continue standard lifestyle measures, including calorie restriction, regular physical activity, and dietary counseling. No pharmacological anti-diabetic or anti-obesity medications were prescribed during the follow-up period unless clinically indicated. Participants were followed prospectively for six months, with clinical assessment at 3 and 6 months post-discontinuation. Body weight, FPG, and HbA1c were reassessed during each visit. Outcome Measures The primary outcomes were: • Change in body weight at six months after discontinuation • Maintenance of diabetes remission, defined as HbA1c <6.5% without glucose-lowering therapy Secondary outcomes included: • Change in fasting plasma glucose • Change in HbA1c levels • Proportion of patients maintaining ≥15% weight loss from baseline . Statistical Analysis Data were analyzed using Statistical Package for Social Sciences (SPSS) version 26.0 (IBM Corp). Quantitative variables including age, weight, BMI, fasting plasma glucose, and HbA1c were expressed as mean ± standard deviation. Qualitative variables such as gender distribution, maintenance of remission, and weight-loss categories were presented as frequencies and percentages. Paired t-test was used to compare pre-discontinuation and six-month follow-up continuous variables. A p-value of <0.05 was considered statistically significant. Ethical Considerations: Approval for the study was obtained from the Institutional Review Board/Ethical Review Committee of South Punjab Hospital, Multan. Written informed consent was obtained from all participants prior to enrollment. Confidentiality of patient information was maintained throughout the study.

The majority of patients belonged to the 41–50 years age group (36%), followed by 31–40 years (28%). Patients aged 51–60 years constituted 24% of the study population, while the least number of participants (12%) were in the 20–30 years age group.

Table 1: Distribution of Patients by Age Group

Among the study participants, males were slightly more predominant, accounting for 56% (n = 28), while females comprised 44% (n = 22) of the total study population.

Table 2: Distribution of Patients by Gender

At 3 months following discontinuation of semaglutide, there were no statistically significant changes in body weight, BMI, fasting plasma glucose, or HbA1c levels compared with values at the time of drug cessation (all p > 0.05). Overall metabolic parameters remained stable during early follow-up.

Table 3: Comparison of Clinical Parameters at Discontinuation vs 3 Months Follow-up

Comparison of clinical parameters at the time of semaglutide discontinuation and after 6 months of follow-up. There was a slight numerical increase in mean body weight from 88.7 ± 10.3 kg to 89.1 ± 10.7 kg; however, this change was not statistically significant (p = 0.21). Similarly, BMI showed a minimal increase from 27.4 ± 2.9 kg/m² to 27.6 ± 3.0 kg/m², which was also statistically non-significant (p = 0.18).

Fasting plasma glucose levels demonstrated a small rise from 94.6 ± 8.9 mg/dL at discontinuation to 96.1 ± 9.2 mg/dL at 6 months, without statistical significance (p = 0.27). Likewise, HbA1c increased marginally from 5.8 ± 0.4% to 6.0 ± 0.6%, but this difference remained statistically insignificant (p = 0.09).

Overall, no clinically meaningful deterioration in weight or glycemic parameters was observed during the 6-month follow-up period after discontinuation of semaglutide, indicating stable metabolic outcomes in the study population.

Table 4: Comparison of Clinical Parameters at Discontinuation vs 6 Months Follow-up

Table 5: Comparison of Clinical Parameters at Discontinuation, 3 Months, and 6 Months Follow-up

The present study evaluated metabolic outcomes following discontinuation of semaglutide in patients with type 2 diabetes mellitus (T2DM) who had achieved substantial weight reduction and diabetes remission. Over a six-month follow-up period, body weight, BMI, fasting plasma glucose, and HbA1c remained largely stable, with no statistically significant deterioration observed. These findings suggest that a subgroup of carefully selected patients may maintain metabolic benefits even after cessation of therapy.

In contrast, most evidence from randomized controlled trials and extension studies indicates that discontinuation of GLP-1 receptor agonists is commonly associated with weight regain and worsening glycemic control. The STEP 1 extension trial demonstrated that participants regained approximately two-thirds of their lost weight within one year after stopping semaglutide, accompanied by deterioration in cardiometabolic parameters [1,3]. Similarly, Rubino et al. reported that withdrawal of semaglutide resulted in progressive weight regain and reversal of metabolic improvements achieved during active treatment [5]. Comparable findings have been reported across other GLP-1 receptor agonist discontinuation studies, supporting the concept that ongoing therapy is generally required to sustain weight loss [6].

However, our findings differ from these large-scale trials, showing stable weight and glycemic control over six months. This discrepancy may be explained by several factors. First, our study included only responders who achieved ≥20% weight loss and diabetes remission prior to discontinuation, representing a highly selected metabolic responder phenotype. Second, structured lifestyle modification was maintained throughout follow-up, which is known to significantly reduce weight regain risk [7]. Third, shorter follow-up duration may not capture delayed metabolic relapse, which often becomes evident after 12–18 months [3,8].

Physiologically, GLP-1 receptor agonists reduce appetite, slow gastric emptying, and enhance satiety through central hypothalamic pathways, leading to sustained caloric deficit during therapy [9]. After discontinuation, these effects diminish, often resulting in increased appetite and energy intake. Nevertheless, substantial prior weight loss may induce partial resetting of metabolic and behavioural homeostasis, improving insulin sensitivity and adipose tissue function, which could explain sustained outcomes in some patients [10].

The maintenance of diabetes remission in 84% of participants further supports this metabolic stability. Evidence from the DiRECT trial has shown that substantial weight loss can restore pancreatic β-cell function and reduce hepatic insulin resistance, enabling sustained glycemic remission in a significant proportion of patients [11]. Our findings are consistent with this hypothesis, suggesting that early intensive weight reduction may induce long-term metabolic benefits even after pharmacotherapy withdrawal.

Despite these encouraging results, variability in long-term outcomes has been widely reported. Observational studies and real-world evidence indicate that a substantial proportion of patients regain weight within 1–2 years of stopping GLP-1-based therapies [12,13]. A recent meta-analysis further confirmed that cessation of GLP-1 receptor agonists is associated with a mean weight regain of 2–6 kg and a rise in HbA1c across most populations [14]. These findings highlight that sustained metabolic success is not universal and may depend on behavioural, biological, and treatment-related factors.

The present study has several limitations. The sample size was relatively small, and the single-center design may limit generalizability. The absence of a control group continuing therapy restricts direct comparative interpretation. Furthermore, the six-month follow-up period may be insufficient to fully assess long-term weight trajectory and metabolic relapse, which typically occurs progressively over a longer duration [3,13].

In summary, this study suggests that a subset of patients with T2DM may maintain significant weight loss and glycemic remission for up to six months following discontinuation of semaglutide. While most existing literature reports weight regain after cessation, our findings indicate that durable metabolic control may be achievable in selected responders. Larger, long-term controlled studies are required to identify predictors of sustained response and optimize treatment discontinuation strategies. Limitations This study has some important limitations. It was conducted on a small sample size from a single center, which may limit the generalizability of the results. The follow-up period of six months is relatively short to fully assess long-term weight regain or glycemic deterioration after stopping semaglutide. In addition, the absence of a control group continuing therapy restricts comparative interpretation. The study also included a selected group of good responders, which may overestimate sustained benefits. Finally, lifestyle adherence was not objectively measured, which could have influenced outcomes.

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