Semaglutide is an established treatment for type 2 diabetes (T2D) and obesity, offering additional cardiovascular and renal benefits. However, gastrointestinal adverse events (AEs) remain a known limitation and have constrained dose levels in earlier clinical trials. A recent phase 2 trial testing doses of up to 16 mg/week suggests that, while higher doses yield further improvements in blood glucose and body weight, there is no clinical justification for exceeding the approved dose of 2 mg/week due to increased frequency of AEs.

Exploring the upper dose limit

The study aimed to investigate whether higher doses of semaglutide could further improve glycaemic and weight outcomes in people living with T2D who are overweight or obese. The parallel-group, double-blind trial was conducted across 82 sites in Greece, Hungary, Poland, and the United States, enrolling 245 participants with T2D and a BMI over 27 kg/m2. All participants were on stable metformin therapy (see Figure 1, left).

Participants were randomised to receive subcutaneous semaglutide once weekly at doses of 2 mg, 8 mg, 16 mg or placebo for 40 weeks, followed by a 9-week follow-up period. Dose escalation was fixed and down-titration or pausing treatment in case of side effects was not permitted.

“The dose escalation scheme was based on earlier modelling, while supporting gradual titration to the target dose levels. The dose was started at 0.29 mg weekly and escalated every four weeks until the target dose was reached. It is important to realise that this is a phase II study, and thus a dose-finding study by nature,” says first-author Vanita R. Aroda, director of Diabetes Clinical Research at Boston’s Brigham and Women’s Hospital and a faculty member at Harvard Medical School.

Modest dose-response observed

The primary endpoint was the change in HbA1c levels. HbA1c levels declined steadily in the semaglutide groups until around week 20, after which they plateaued. The estimated treatment difference between the 16 mg and 2 mg doses was non-significant at -0.3 percentage points (95 % confidence interval [CI]: -0.7 to 0.2; p = 0.245; see Figure 1, top right).

In contrast, weight loss demonstrated a clearer dose-response relationship. Body weight decreased continuously up to week 40 across all semaglutide groups. The mean percentage weight reductions were -7.3 %, -8.3 % and -10.8 % for the 2 mg, 8 mg and 16 mg doses respectively, compared to -2.0 % with placebo (treatment policy estimand, i.e. based on the in-study observation period, meaning rescue medication also influences HbA1c levels). The difference in weight loss between the 16 mg and 2 mg groups was statistically significant at -3.4 kg (p = 0.011; see Figure 1, top right).

The hypothetical estimand (on-treatment without rescue medication) showed a statistically significant difference between the 16 mg and 2 mg groups, for both the HbA1c reduction and a weight loss with -0.5 percentage points (95 % CI: -1.0 to -0.1; p = 0.015) and -4.5 kg (95 % CI: -7.6 to -1.4; p = 0.004), respectively.

Dose-response modelling further supported these findings, particularly highlighting the potential for incremental weight loss with higher semaglutide doses. Mean weight loss exceeded 5 % in all semaglutide groups, surpassing 10 % in the 16 mg group.

Adverse events: Dose-dependent and limiting

Overall, 84.5 % of participants who completed the treatment finished without requiring rescue medication. However, tolerability issues led to a higher rate of treatment discontinuation in the 8 mg and 16 mg groups (23 % and 18 %, respectively; see Figure 1, bottom right). Most discontinuations occurred in the first half of the trial and were due to gastrointestinal AEs, including nausea, vomiting, and diarrhoea.

These side effects occurred more frequently than in previous phase III trials, a finding that the authors attribute to the enforced dose escalation scheme. “Higher gastrointestinal side effects are typically seen at higher doses of GLP-1 RA-based therapy, and this was also seen here. Dose modifications, such as down-titration or pauses in titration, were not permitted. Hence, if the specified treatment dose was not tolerated, treatment was discontinued,” notes Aroda. “This is part of the phase II dose-finding study design in order to understand the efficacy and safety of specific dosing regimens and titrations.”

No severe hypoglycaemic episodes were recorded. Nine serious AEs occurred, including a case of acute cholecystitis in the 16 mg group.

Clinical implications: Person-centred care remains key

The study set out to analyse the dose-response relationship of semaglutide in T2D and obesity, testing doses up to eight times higher than the currently approved maximum.

“The results confirmed the benefit-risk profile of currently approved doses of semaglutide for clinically meaningful glucose and weight management in people with T2D. Higher doses provided a modest additional glucose-lowering effect and additional weight loss, though there were more adverse events. The current maximal dose of semaglutide approved for treatment of T2D remains at 2 mg,” Aroda summarises. She comments: “While this is a phase II dose-finding study and thus follows a very specific protocol, in clinical care one follows a person-centred approach and titrates the incretin-based therapy for individualised effect. It is important to keep the person-centred care goals front and centre while one balances the efficacy and safety of the therapeutic approach.”

Given the shared pathophysiological mechanisms between obesity and T2D, optimising treatments for both conditions remains critical. While semaglutide offers benefits in terms of glycaemic control, weight and cardiovascular risk, this study confirms that, for T2D patients with obesity, the 2 mg/week dose is the highest that can be justified for glycaemic management. Further insights may emerge from ongoing studies, such as a phase III trial investigating the use of a 7.2 mg dose of semaglutide for weight management in adults with T2D and obesity (NCT05649137).

Key Points:

• In people with T2D and obesity, increasing semaglutide beyond 2 mg per week results in modest improvements in glycaemic control and greater weight loss, but also significantly more gastrointestinal adverse events.
• The strongest dose-response was observed for weight loss. Participants on a weekly dose of 16 mg lost an average of over 10 % body weight.
• Treatment discontinuations were more frequent with the 8 mg and 16 mg doses, primarily due to gastrointestinal adverse effects.
• The approved 2 mg/week dose of semaglutide remains the upper limit recommended for balancing efficacy and safety for the treatment of type 2 diabetes.

To read this paper visit this link.

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.