Semaglutide in obesity and type 2 diabetes: A review of clinical trial evidence from 1 to 5 semaglutide treatment effect in people with obesity program

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are widespread health concerns that often coexist, contributing to increased cardiometabolic risks and premature death. Despite advancements in both lifestyle interventions and medical treatments, achieving lasting weight reduction and stable glycemic control remains a major clinical challenge. This review examines findings from the semaglutide treatment effect in people with obesity 1 (STEP) 1–5 trials, which assessed the effectiveness, safety, and long-term outcomes of once-weekly semaglutide 2.4 mg for weight management in adults. These trials included individuals with and without T2DM, enabling comparison across different populations and interventions. In nondiabetic participants (STEP 1, 3, and 4), semaglutide led to average weight reductions between 10% and 17%, while in patients with T2DM (STEP 2), the reduction was around 10%. The inclusion of intensive behavioral therapy in STEP 3 further enhanced weight loss outcomes. Results from STEP 4 highlighted notable weight regain following treatment withdrawal, reflecting the relapsing nature of obesity. STEP 5 confirmed semaglutide’s ability to maintain significant weight loss (~15%) and improve metabolic health over a 2-year period. The most common side effects were gastrointestinal in nature but were generally manageable and nonsevere. Collectively, these trials support semaglutide 2.4 mg as an effective and sustainable option for managing obesity and overweight, including in people with T2DM. The data also emphasize the importance of combining pharmacological therapy with lifestyle modifications and recognize obesity as a long-term condition that necessitates continuous treatment.

Introduction

Diabetes and obesity – Global burden

Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder where the body cannot effectively use insulin, resulting in elevated blood glucose levels. It has emerged as a major public health challenge globally.[1] The worldwide prevalence of diabetes has risen dramatically – from 108 million in 1980 to 422 million by 2014. Among adults over the age of 18 years, diabetes prevalence increased from 4.7% in 1980 to 8.5% in 2014, and the World Health Organization (WHO) estimates that this number could reach 439 million by 2030, accounting for nearly 10% of the adult population.[2] Moreover, global T2DM-related deaths have soared from 238,100 to 723,700 between 1990 and recent years – reflecting a staggering 203.9% rise.[1]

Obesity is a well-established risk factor for T2DM. Excess adiposity – especially visceral fat – disrupts insulin signaling pathways and glucose metabolism, eventually resulting in hyperglycemia.[3] It is estimated that 80%–90% of individuals living with type 2 diabetes are either overweight or obese.[4] The WHO defines obesity as an “abnormal or excessive fat accumulation that may impair health.”[5] As of 2024, 35 million children under 5 years old were classified into overweight. In 2022, over 390 million children and adolescents aged 5–19 were overweight, including 160 million who were obese.[6] Alarmingly, one in every eight individuals globally now lives with obesity – a figure that has more than doubled since 1990. These alarming trends, highlighted by the Global Burden of Disease Study 2019,[7] signal a growing public health crisis that urgently requires focused interventions to manage both obesity and diabetes effectively.

Limitations of current diabetes and weight management strategies

Lifestyle modifications remain the foundation of weight management; however, by itself, it often yields only moderate weight loss that is difficult to sustain. This challenge stems from neuroendocrine feedback mechanisms that drive increased hunger, reduced satiety, and possible reductions in energy expenditure, all of which encourage weight regain. Despite continued innovations in both pharmacological and nonpharmacological approaches, substantial gaps persist in the treatment of obesity and type 2 diabetes. Many approved anti-obesity drugs such as orlistat, liraglutide, and phentermine/topiramate – are linked to modest reductions in weight (typically around 5%–10% of baseline weight), but their effectiveness is often nullified by gastrointestinal side effects, psychiatric concerns, or cardiovascular risks, which limit their long-term use and patient adherence.[7,8,9]

Similarly, standard glucose-lowering medications such as sulfonylureas and insulin, while effective in managing hyperglycemia, are frequently associated with undesirable outcomes such as weight gain and hypoglycemia. Importantly, these agents do not address underlying disease progression or related complications such as cardiovascular disease.[10,11] Lifestyle interventions, although essential, often suffer from poor long-term adherence, socioeconomic limitations, and high relapse rates.[12] These ongoing limitations highlight the importance of need of a safer, more effective, and sustainable therapeutic option – especially those that offer integrated benefits for both blood sugar control and weight reduction.

The rise of glucagon-like peptide-1 receptor agonists and the emergence of semaglutide

Over the last two decades, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the therapeutic landscape for both type 2 diabetes and obesity. Initially intended to improve blood glucose management, through mechanisms such as stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying, these agents were later found to offer substantial benefits in appetite control, weight loss, and cardiovascular health.[13,14,15] Early GLP-1 RAs such as exenatide and liraglutide helped validate this drug class, although their use was often limited by gastrointestinal side effects and the inconvenience of frequent dosing.

Semaglutide, a next-generation long-acting GLP-1 RA with high receptor affinity and once-weekly dosing, represents a major advancement in this therapeutic class.[16] Initially approved for the treatment of type 2 diabetes under the tradename Ozempic, later gained regulatory approval for chronic weight management as Wegovy. Data from large-scale clinical programs – including SUSTAIN, PIONEER, and semaglutide treatment effect in people with obesity (STEP) – consistently demonstrate semaglutide’s superiority in both glycemic and weight outcomes compared to standard therapies.[17,18,19] Semaglutide is now positioned as a leading pharmacological agent in the emerging field of metabolic therapeutics, benefiting both diabetic and nondiabetic population.

Rationale for the semaglutide treatment effect in people with obesity program

The STEP clinical trial program is a series of international, multicenter, and randomized controlled trials to assess the safety and efficacy of semaglutide 2.4 mg once weekly for weight management in individuals with overweight or obesity – with or without type 2 diabetes. These trials aim to compare semaglutide against placebo in terms of weight loss outcomes, safety, and tolerability in adults requiring pharmacological obesity management. Early insights from prior diabetes-focused studies (SUSTAIN and PIONEER) already suggests semaglutide’s substantial weight loss effects, prompting researchers to formally test its use in broader metabolic contexts, including nondiabetic patients and those undergoing behavioral interventions. The STEP program consists multiple individual trials – namely, STEP 1 through STEP 5, each investigating a different clinical scenario like long-term treatment efficacy, the role of behavioral support, withdrawal outcomes, and cardio-metabolic parameters.

Pharmacological Profile of Semaglutide

GLP-1 is a key incretin hormone secreted by intestinal L-cells in response to food intake. It facilitates glucose-dependent insulin release and concurrently suppresses glucagon secretion, thereby maintaining glycemic control.[20] GLP-1 RAs are therapeutic agents that mimic these physiological effects, promoting insulin secretion and reducing glucagon levels, particularly in hyperglycemic states.[21] Among the latest and most promising agents in this class is semaglutide, available in both subcutaneous and oral formulations.[22] Structurally, semaglutide is a modified analog of human GLP-1, retaining approximately 94% similarity with the native peptide.[23,24]

Semaglutide’s pharmacological enhancements arise from three structural modifications Figure 1

Figure 1.

Chemical structure of semaglutide. ©2020 Journal of the Association of Physicians of India. Used with permission[25]

1. Substitution at position 8: Alanine is replaced with α-aminoisobutyric acid protecting the peptide from degradation by the enzyme dipeptidyl peptidase-4[23,24]

2. Acylation at position 26: The attachment of a C-18 fatty acid chain to the lysine residue promotes strong and prolonged binding to albumin, extending the drug’s half-life

3. Substitution at position 34: The lysine is replaced with arginine, which helps to ensure that fatty acid chain binds at the correct site, preventing wrong attachment and maintaining structural integrity.

These biochemical alterations significantly increase the molecular stability of semaglutide, resulting in an extended half-life of approximately 160 h, thereby enabling once-weekly dosing.[25]

Mechanism of action

Pancreatic effects

Figure 2 demonstrates MOA by showing effects of GLP-1 analogs enhance glucose-dependent insulin secretion by stimulating pancreatic β-cells, leading to increase in insulin levels in response to elevation in blood glucose. Simultaneously, they suppress glucagon release from α-cells, thereby reducing hepatic glucose output. This dual action promotes better glycemic control with a lower risk of hypoglycemia compared to traditional insulin secretagogues.

Figure 2.

Mechanism of action of glucagon-like peptide-1 receptor analogs in glucose regulation and weight management

Central nervous system effects

GLP-1 receptors are expressed in the hypothalamus, where GLP-1 analogs act to suppress appetite and enhance satiety. These central effects result in reduction in caloric intake and decreased cravings for food, contributing to body weight reduction.

Gastrointestinal effects

Semaglutide and other GLP-1 analogs delay gastric emptying through vagal afferent signaling. This slows the rate of nutrient entry into the small intestine, attenuating postprandial glucose excursions. Although this effect may diminish over time (tachyphylaxis), it plays a key role in early therapy.

Hepatic effects

The inhibition of glucagon secretion reduces hepatic gluconeogenesis and glycogenolysis, leading to decreased plasma glucose concentrations. This contributes to the overall glucose-lowering effect of GLP-1 analogs.

Semaglutide Treatment Effect in People with Obesity Program

To comprehensively assess the efficacy, safety, and clinical applicability of semaglutide 2.4 mg for chronic weight management, the STEP clinical trial program was initiated. This global, multi-phase series of trials evaluates semaglutide across diverse populations and clinical contexts, both with and without type 2 diabetes.

Table 1 compares the key characteristics, targeted populations, and major outcomes from the STEP 1–5 clinical trial program.

Table 1.

Key characteristics and major outcomes of the semaglutide treatment effect in people with obesity 1–5 clinical trials of semaglutide

Trial	Target population	Duration (weeks)	Primary purpose	Key findings/notes
STEP 1	Adults with obesity or overweight; no diabetes	68	Efficacy of semaglutide 2.4 mg for weight loss	Mean weight reduction of 14.9% versus 2.4% with placebo. Lifestyle intervention included[18] (Wilding et al., 2021)
STEP 2	Adults with obesity or overweight; with type 2 diabetes	68	Evaluate weight loss and glycemic control	Semaglutide caused 9.6% weight loss versus 3.4% with placebo. HbA1c also significantly reduced[26] (Davies et al., 2021)
STEP 3	Obese or overweight adults + comorbidity; no diabetes	68	Evaluate effect of semaglutide + intensive behavioral therapy	16.0% weight loss versus 5.7% placebo; with counseling and diet plan[27] (Wadden et al., 2021)
STEP 4	Adults after 20-week run-in with semaglutide; no diabetes	68	Assess effect of continuing versus stopping semaglutide	Continued semaglutide led to sustained weight loss versus regain with placebo[28] (Rubino et al., 2021)
STEP 5	Obese/overweight adults without diabetes	104	Evaluate long-term weight management and safety	Semaglutide resulted in 15.2% weight loss at 2 years versus 2.6% with placebo[29] (Garvey et al., 2022)

HbA1c=Glycated hemoglobin, STEP=Semaglutide treatment effect in people with obesity

Collectively, the trials demonstrate a consistent trend of clinically meaningful and sustained weight loss, with reductions ranging from ~ 10% to over 16%, depending on the study design and adjunct interventions. STEP 1 and STEP 3 highlight the additive benefit of behavioral therapy and lifestyle modification, while STEP 4 confirms the necessity of continued treatment to maintain weight loss. In diabetic populations (STEP 2), while weight loss was modestly attenuated, the trial underscored the dual benefit of glycemic control and weight reduction. Notably, STEP 5 extended the evidence to a 2-year horizon, reinforcing the long-term efficacy and tolerability of semaglutide. This comprehensive portfolio highlights semaglutide’s potential as a cornerstone therapy in the management of obesity and related comorbidities.

Semaglutide treatment effect in people with obesity-1

The STEP 1 trial (NCT03548935) is a landmark phase III, randomized, double-blind, and placebo-controlled study evaluating the efficacy of once-weekly subcutaneous semaglutide 2.4 mg in adults with obesity or overweight (BMI ≥30 kg/m² or ≥27 kg/m² with ≥1 weight-related comorbidity) without diabetes. Conducted across 129 sites in 16 countries, the trial enrolled 1961 participants, randomized in a 2:1 ratio to semaglutide or placebo, both combined with lifestyle intervention.

Design and treatment regimen

The treatment spanned 68 weeks, including a 16-week dose-escalation period, with semaglutide initiated at 0.25 mg and titrated up to 2.4 mg weekly. Lifestyle intervention included monthly counseling promoting a 500 kcal/day energy deficit and 150 min/week of physical activity. After the treatment phase, a subset of participants from five countries (Canada, Germany, Japan, UK, and US) entered a 52-week off-treatment extension phase. This group, referred to as the extension analysis set (ExAS), included 327 participants (228 semaglutide and 99 placebo).

Treatment effects and postdiscontinuation monitoring

The STEP 1 trial primarily focused on evaluating the effect of semaglutide on body weight reduction over a 68-week treatment period. The main outcome assessed was the percentage change in body weight from baseline to week 68.

In the subsequent extension phase, the investigation expanded to include two key areas:

Assessment of long-term outcomes

Tracking changes in body weight and cardiometabolic risk markers (e.g. blood pressure, lipids, and hemoglobin A1c [HbA1c]) during the 52 weeks following withdrawal of both semaglutide and lifestyle support.

Consistency of treatment effects

Comparing outcomes observed in the extension population (ExAS) with those from the overall trial cohort (full analysis set) to determine the generalizability of treatment responses.

Key findings

Weight outcomes

These findings demonstrate the marked efficacy of semaglutide in achieving clinically meaningful weight loss during active treatment. However as demonstrated in Figure 3, the trend toward weight regain after stopping therapy highlights the importance of continued treatment for sustaining weight reduction in individuals with obesity. Long-term maintenance strategies may be necessary to prevent relapse and support durable outcomes.

Figure 3.

Body weight variation over time in semaglutide treatment effect in people with obesity-1 trials. By the end of the 68-week active treatment phase, individuals receiving semaglutide experienced a substantial average weight reduction of 17.3%, significantly outperforming the 2.0% reduction seen in the placebo group. After the discontinuation of treatment and lifestyle support, weight regain occurred in both groups over the following year. Semaglutide participants regained an average of 11.6 percentage points, while those in the placebo group regained 1.9 points. This resulted in a net weight loss of 5.6% in the semaglutide group compared to 0.1% in the placebo group at week 120

Cardio-metabolic markers

Improvements in blood pressure, lipids (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and VLDL cholesterol), triglycerides, C-reactive protein (CRP), and HbA1c observed at week 68 with semaglutide largely regressed towards baseline as shown in Figure 4 by week 120. However, residual benefits in HDL, triglycerides, and CRP persisted relative to place.

Figure 4.

Change in cardiometabolic factors in semaglutide treatment effect in people with obesity 1 trial. Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]): Initially reduced by 6.2% (SBP) and 3.7% (DBP) during treatment, these values rebounded to above baseline by week 120 (+1.6% SBP, +1.2% DBP), and showing loss of benefit after stopping treatment. Hemoglobin A1c: Improved by 8.8% during semaglutide use, reflecting better glycemic control. Although it partially reversed post-treatment (−1.8%), a small net benefit remained. C-reactive protein: Marked reduction during treatment (−56.6%) indicates a strong anti-inflammatory effect. Even after discontinuation, a significant reduction (−38.0%) was maintained, suggesting longer-lasting benefit. Low-density lipoprotein cholesterol: Showed modest improvement (−4.6%) that largely persisted after treatment withdrawal (−4.3%). High-density lipoprotein Cholesterol: Increased during treatment (+7.1%) and remained elevated (+3.5%), indicating a sustained positive effect on cardioprotective lipid levels

Glycemic control

Among participants who had prediabetes at the start of the trial, a notable 93.6% achieved normoglycemia by week 68 with semaglutide treatment, in contrast to 41.5% in the placebo group. By week 120, following discontinuation of therapy, the proportion maintaining normoglycemia decreased to 43.3% in the semaglutide group and 34.0% in the placebo group, indicating partial relapse.

Subgroup observations

It further revealed that individuals who lost more weight during the active treatment phase tended to regain more after stopping therapy – yet they still maintained a higher net reduction in body weight compared to those with less initial loss. In addition, participants who began the trial with normal glucose levels achieved greater overall weight reduction than those with prediabetes, suggesting baseline metabolic status influences the long-term outcomes.

Clinical implications

The STEP 1 trial provides strong evidence supporting the use of semaglutide 2.4 mg as an effective intervention for promoting significant weight loss and metabolic improvements in individuals with overweight or obesity. However, findings from the follow-up period reinforce the concept that obesity is a chronic, relapsing condition – and that discontinuing pharmacologic treatment often leads to the reversal of clinical benefits.

The observed weight regain and decline in cardiometabolic improvements following treatment cessation reflect underlying physiological mechanisms that resist weight loss maintenance. These findings lend further support to the growing perspective that long-term, sustained pharmacotherapy may be necessary as a standard approach for managing obesity and its associated health risks.

Semaglutide treatment effect in people with obesity 2

Overview and study design

The STEP 2 trial was a phase 3 (ClinicalTrials. gov Identifier: NCT03552757), randomized, double-blind, placebo-and active-controlled study designed to assess the efficacy and safety of once-weekly semaglutide 2.4 mg for weight management in adults with overweight or obesity and type 2 diabetes. A total of 1210 participants were randomly assigned to three groups: semaglutide 2.4 mg, semaglutide 1.0 mg (the standard dose for diabetes), or placebo. All groups also received standardized lifestyle counseling involving dietary guidance and physical activity goals.

Key findings

Weight reduction

The graph in Figure 5 demonstrates, that a significantly higher percentage of participants receiving semaglutide 2.4 mg achieved meaningful weight loss compared to those on 1.0 mg or placebo. Specifically, the 2.4 mg dose led to the greatest success across all thresholds – ≥5%, ≥10%, and ≥15% weight loss – with nearly seven out of ten participants reaching at least a 5% reduction in body weight. This visual underscores the dose-related impact of semaglutide and highlights its strong potential as a more effective intervention for long-term weight management in individuals with obesity and type 2 diabetes.

Figure 5.

The percentage of patients who achieved ≥5%, ≥10%, and ≥15% weight loss after 68 weeks in the semaglutide treatment effect in people with obesity 2 trial are compared across three treatment groups: Semaglutide 2.4 mg showed the highest success rates, with nearly 69% of participants achieving at least 5% weight loss, and over 25% achieving ≥15% reduction. Semaglutide 1.0 mg also led to weight loss but to a lesser extent with about 57% of participants achieving ≥5% reduction. Placebo group outcomes were notably lower across all thresholds

Glycemic control trends as explained in Figure 6 shows:

Figure 6.

The proportion of participants achieving glycemic control, defined as hemoglobin A1c (HbA1c) ≤6.5%, at week 68 in the semaglutide treatment effect in people with obesity 1 trial. Participants treated with semaglutide 2.4 mg had the highest rate of achieving target HbA1c levels (67.5%), followed closely by those receiving semaglutide 1.0 mg (60.1%). In contrast, only 15.5% of participants in the placebo group reached this level of glycemic control

• Mean HbA1c reduction was −1.6% with semaglutide 2.4 mg versus −0.4% with placebo

• 67.5% of patients on 2.4 mg achieved HbA1c ≤6.5%, compared to 60.1% on 1.0 mg and only 15.5% on placebo

• Fasting plasma glucose also decreased significantly more with semaglutide 2.4 mg than with placebo.

Cardiometabolic and physical parameters

• Semaglutide 2.4 mg led to greater reductions in waist circumference, systolic blood pressure, CRP, triglycerides, and VLDL cholesterol compared to placebo

• Improvements in quality of life scores (SF-36 v2 and IWQOL-Lite-CT) were also more pronounced in the semaglutide 2.4 mg group.

Safety profile

• Gastrointestinal side effects (e.g., nausea, diarrhea) were more common in the semaglutide groups, particularly at the 2.4 mg dose, but were mostly mild or moderate

• Rates of serious adverse events and hypoglycemia were similar across all groups

• No unexpected safety concerns were reported.

Semaglutide treatment effect in people with obesity-3

Study background and objective

The STEP 3 trial (ClinicalTrials.gov Identifier: NCT03611582) was designed to evaluate whether once-weekly semaglutide 2.4 mg, when used in combination with intensive behavioral therapy (IBT) and an initial low-calorie diet, would result in superior weight loss outcomes compared to placebo. This approach reflects a more aggressive lifestyle intervention model, with the intent to replicate optimal real-world support for individuals with overweight or obesity but without diabetes.

Study design

This was a randomized, double-blind, placebo-controlled, multicenter phase 3 trial conducted over 68 weeks at 41 U.S. sites. A total of 611 adults with a BMI ≥30, or ≥27 with at least one comorbidity (excluding diabetes), were randomized in a 2:1 ratio to receive semaglutide (n = 407) or placebo (n = 204), alongside a structured behavioral and dietary program. The intervention included:

• An 8-week low-calorie diet (1000-1200 kcal/day)

• 30 individual IBT sessions over the 68-week period

• A gradual increase in physical activity from 100 to 200 min/week.

Primary and secondary endpoints

• Primary endpoints

  • Percent change in body weight at week 68

  • Proportion of participants achieving ≥5% weight loss.

• Key secondary outcomes

  • Proportion achieving ≥10%, ≥15%, and ≥20% weight loss

  • Changes in waist circumference, blood pressure, HbA1c, lipid profile, CRP, and quality-of-life scores.

Key findings

Weight loss

Participants in the semaglutide group achieved a mean weight reduction of 16.0%, compared to 5.7% in the placebo group. As shown in Figure 7, a striking 86% of semaglutide recipients lost ≥5% of body weight, compared to 47.6% in the placebo group. Moreover, 75.3%, 55.8%, and 35.7% of semaglutide participants achieved ≥10%, ≥15%, and ≥20% weight loss, respectively.

Figure 7.

Proportion of participants who reached ≥ 5%, ≥10%, ≥15%, and ≥ 20% weight loss over 68 weeks in the semaglutide treatment effect in people with obesity 1 trial: Participants receiving semaglutide 2.4 mg consistently outperformed those on placebo across all thresholds. Nearly 87% of those in the semaglutide group lost at least 5% of their body weight, while over one-third achieved a reduction of 20% or more. In contrast, fewer than 48% of placebo recipients achieved 5% loss, and only 3.2% met the 20% threshold

Cardiometabolic markers

1. Waist circumference: Reduced by 14.6 cm with semaglutide vs 6.3 cm with placebo

2. Systolic blood pressure: Dropped by 5.6 mm Hg (vs. 1.6 mm Hg placebo)

3. CRP: Decreased by 59.6% in semaglutide group versus 22.9% in placebo

4. LDL and triglycerides: Both significantly improved with semaglutide.

Glycemic parameters

Modest but statistically significant improvement as shown in Figure 8 HbA1c (−0.51%) and fasting glucose (−6.7 mg/dL) were observed.

Figure 8.

Participants receiving semaglutide had an average hemoglobin A1c drop of −0.51%, significantly more than the − 0.10% reduction seen in the placebo group. This indicates improved long-term glycaemic control, even in participants without diabetes fasting glucose reduction: The semaglutide group experienced a −6.7 mg/dL reduction in fasting plasma glucose, compared to just −0.3 mg/dL with placebo. This reflects improved baseline glucose regulation and insulin sensitivity

Quality of life

While physical functioning (SF-36) improved similarly in both groups, the mental component score improved more with semaglutide.

Safety profile

• Gastrointestinal events (nausea, vomiting, diarrhea) were the most common side effects, affecting 82.8% of semaglutide users versus 63.2% in the placebo group. Most were mild and transient

• Serious adverse events were more frequent with semaglutide (9.1% vs. 2.9%), largely due to gallbladder-related issues, likely related to rapid weight loss

• No deaths or cases of acute pancreatitis or medullary thyroid carcinoma were reported.

Interpretation and clinical relevance

The STEP 3 trial underscores that adding semaglutide 2.4 mg to a high-intensity lifestyle intervention leads to significantly greater weight loss and metabolic improvement than IBT alone. This trial is particularly relevant for settings aiming to optimize nonsurgical obesity management. The findings also highlight the importance of pharmacologic support in achieving clinically meaningful weight loss thresholds, especially in individuals who have previously failed diet and lifestyle approaches.

Semaglutide treatment effect in people with obesity 4

Study background and desigm

The STEP 4 trial specifically addressed a clinically relevant question: What happens to weight loss maintenance when semaglutide treatment is stopped after initial success? STEP 4 was an international, multicenter, phase 3a randomized withdrawal study (ClinicalTrials.gov Identifier: NCT03548987) involving adults with overweight or obesity but without type 2 diabetes. Initially, all participants received open-label semaglutide (starting at 0.25 mg/week, titrated up to 2.4 mg/week) for 20 weeks to achieve maximum tolerated dosing. By the end of this period, participants had lost an average of 10.6% of their initial body weight. Eligible participants who completed the run-in phase were then randomly assigned in a 2:1 ratio to either continue semaglutide or switch to placebo for an additional 48 weeks. All participants also received structured lifestyle counseling with dietary and physical activity goals throughout the trial.

Key findings

The primary outcome was the percentage change in body weight from the start of randomization (week 20) to the end of the trial (week 68). The as illustrated in Figure 9 a clear divergence:

Figure 9.

It illustrates the sustained weight loss achieved with continued once-weekly semaglutide (2.4 mg) versus the marked weight regain that occurred when treatment was withdrawn and replaced with placebo. During the 20-week run-in phase, all participants lost about 10.6% of their initial body weight. After randomization at week 20, those who stayed on semaglutide continued to lose weight, reaching an average total loss of around 17.4% by week 68. In contrast, participants who stopped semaglutide regained a significant portion of weight, ending with a net loss of only ~ 5% from baseline. This pattern strongly demonstrates the chronic, relapsing nature of obesity, highlighting the necessity for ongoing pharmacological treatment to maintain weight loss. The dashed line shows the clear separation point at week 20 when participants were randomized to either continue or withdraw the medication

• Those who continued semaglutide lost an additional average of 7.9% of their body weight

• Those who switched to placebo regained about 6.9% of their weight

• This resulted in an estimated difference of approximately 14.8 percentage points (95% confidence interval: −16.0 to −13.5), favoring continued treatment (P < 0.001).

Significant improvements were also seen in secondary outcomes, including reductions in waist circumference and systolic blood pressure and improvements in physical functioning scores. Importantly, the proportion of participants achieving clinically meaningful weight loss thresholds (≥5%, ≥10%, ≥15%, and ≥20% from baseline) remained substantially higher in the semaglutide group compared to placebo.

Safety profile

As expected, gastrointestinal side effects (mainly nausea, diarrhea, and constipation) were among the most frequent adverse events reported, affecting approximately 42% of participants continuing semaglutide compared to 26% in the placebo group. Nevertheless, discontinuation due to adverse effects was low and similar between groups (<3%).

Clinical significance

The STEP 4 trial provides robust evidence that obesity behaves as a chronic, relapsing condition: discontinuing effective pharmacologic therapy leads to significant weight regain, even when lifestyle support continues. These findings support the need for long-term, possibly indefinite, medical treatment in combination with lifestyle measures to sustain weight loss and its associated health benefits.

Semaglutide treatment effect in people with obesity-5

It was a multinational, phase 3, randomized, double-blind, placebo-controlled trial, (ClinicalTrials. gov Identifier: NCT03693430) conducted at 41 sites across five countries. A total of 304 adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m² with at least one weight-related comorbidity) but without diabetes were randomly assigned 1:1 to receive semaglutide or placebo, alongside standardized lifestyle counseling on diet and physical activity.

The co-primary endpoints as shown in Figure 10:

Figure 10.

Over the 104-week treatment period, participants treated with semaglutide achieved a mean weight loss of 15.2%, compared with 2.6% in the placebo group – an estimated treatment difference of −12.6 percentage points (P < 0.0001). 77.1% of participants in the semaglutide group lost ≥5% of their baseline weight, compared with 34.4% in the placebo group. More ambitious weight loss thresholds were also reached:

• ≥10% weight loss: 61.8% (semaglutide) versus 13.3% (placebo)

• ≥15% weight loss: 52.1% versus 7.0%

• ≥20% weight loss: 36.1% versus 2.3%

• Percentage change in body weight from baseline to week 104

• Proportion achieving at least 5% weight loss at week 104.

Key findings

The trajectory of weight loss demonstrated an initial robust decline, which plateaued around week 60 and was largely maintained through the 2-year period – underscoring the drug’s ability to prevent weight regain with continued use.

Beyond weight reduction, semaglutide showed significant improvements in waist circumference, systolic and diastolic blood pressure, fasting glucose, HbA1c, insulin resistance, lipids, and inflammatory markers such as CRP – all contributing to a more favorable cardiometabolic profile.

Safety profile

Gastrointestinal side effects (including nausea, diarrhea, and constipation) were the most commonly reported adverse events, affecting ~82% of semaglutide-treated participants compared to ~54% with placebo. These events were generally mild to moderate and occurred mostly during dose escalation. Serious adverse events were slightly less common with semaglutide than placebo.

Importantly, high adherence and completion rates (over 92% attended the end-of-trial safety visit) reinforce the feasibility of long-term treatment.

Clinical significance

The STEP 5 trial demonstrates that semaglutide 2.4 2., when combined with behavioral intervention, delivers clinically significant and durable weight loss over 2 years, with consistent cardiometabolic benefits. These results reinforce the role of semaglutide as a long-term treatment option for obesity, providing evidence that meaningful weight loss can be sustained beyond 1 year, a challenge with many other interventions.

Conclusion

The STEP 1-5 clinical trials provide robust evidence that once-weekly semaglutide 2.4 mg, when combined with lifestyle intervention, delivers clinically significant weight loss and cardiometabolic benefits for adults with overweight or obesity, including those with type 2 diabetes. Collectively, these studies demonstrate consistent and superior outcomes compared to lifestyle intervention alone, addressing one of the most pressing challenges in obesity management: achieving and sustaining meaningful weight loss.

STEP 1, 3, and 4 confirmed that semaglutide induces average weight losses of 10%–17% in people without diabetes – far exceeding typical results with behavioral therapy alone. STEP 2 extended this evidence to individuals with type 2 diabetes, who achieved moderate but still significant weight reductions, despite the known physiological barriers to weight loss in this population. Notably, STEP 3 illustrated that combining semaglutide with IBT and an initial low-calorie diet yields the greatest weight reductions, emphasizing the additive effect of lifestyle support.

Long-term durability is a crucial factor, and the STEP 4 withdrawal study showed that discontinuing semaglutide leads to considerable weight regain, mirroring the chronic and relapsing nature of obesity. In contrast, the STEP 5 trial demonstrated that sustained treatment over 2 years results in maintained weight loss averaging around 15% with persistent improvements in key cardiometabolic markers.

Across the STEP program, semaglutide’s tolerability profile has remained acceptable, with gastrointestinal side effects being the most common but typically mild-to-moderate in severity. Overall, these findings highlight semaglutide’s potential to close the gap between short-term weight loss and its long-term maintenance – a gap that has historically limited the impact of obesity pharmacotherapy.

In summary, semaglutide 2.4 mg represents a significant advance in the medical treatment of obesity and type 2 diabetes, offering patients an effective option for achieving substantial, sustained weight loss, improving cardiometabolic health, and reducing obesity-related complications. The STEP trials collectively reinforce the importance of long-term, individualized pharmacotherapy in the comprehensive management of these chronic metabolic diseases.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.