A New Bar for Pharmacologic Weight Loss: Type 2 Diabetes Prevention

The incidence of type 2 diabetes (T2D) has risen in parallel with obesity trends (1,2), resulting in considerable morbidity, mortality, and costs of care (3). Intensive lifestyle (4) and bariatric surgery (5,6) interventions have demonstrated durable effectiveness in preventing T2D but remain greatly underutilized (7–10). Glucose-lowering therapies such as metformin have also shown some promise, although none are specifically approved by the U.S. Food and Drug Administration for this purpose and the risks and benefits of long-term use need to be considered (11). In contrast, there is limited evidence for pharmacologic weight loss therapies to prevent T2D (12–15).

In this issue of Diabetes Care, Perreault et al. (16) present a post hoc analysis of the metabolic effects of weekly semaglutide 2.4 mg among participants with prediabetes in the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials. Participants were obese (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) and had one or more weight-related comorbidities but did not have T2D. All studies were conducted on a background of traditional lifestyle interventions (STEP 1 and 4) or intensive behavioral therapy (STEP 3). By week 68, the percentage of participants with evidence of normoglycemia with semaglutide was 84.1% vs. 47.8% in the placebo group, P < 0.0001, in STEP 1; 89.5% vs. 55%, P < 0.0001, in STEP 3; and 89.8% vs. 70.4%, P < 0.0001, in STEP 4. Not surprisingly, change in glycemic status was associated with weight loss. Semaglutide afforded greater reductions in HbA_1c, fasting glucose, and HOMA of insulin resistance but not HOMA of β-cell function compared with placebo.

The strengths of this analysis include a vigorous double-blinded randomized design across a large international study population. Moreover, there was robust weight loss in the placebo arms, underscoring the effectiveness of adjunctive lifestyle changes.

Weaknesses relate to differences in study design that precluded pooled analyses and use of post hoc outcomes. The study population was mostly White and female, and thus the findings may not apply to more diverse populations. Importantly, there was no washout period, making it difficult to separate glycemic effects of semaglutide from overall glycemic status, weight loss, and underlying pathophysiology. Of note, there were persistent reductions in HbA_1c and glucose following cessation of semaglutide in the placebo arm after the run-in phase of STEP 4, suggesting enduring benefit beyond the glycemic effects of semaglutide per se. By comparison, at the end of the Diabetes Prevention Program, an oral glucose tolerance test was repeated 1–2 weeks after cessation of metformin, demonstrating that 26% of the diabetes prevention effect did not persist after cessation of metformin (17). Moreover, it is known that glycemic and weight loss benefits wane after stopping glucagon-like peptide 1 receptor agonists in individuals with obesity, prediabetes, and T2D (18–20). Likewise, it is not possible to determine whether the glycemic changes were due to weight loss or due to specific effects of the drug. In a post hoc analysis of 4,725 participants in randomized controlled trials assessing liraglutide 3 mg versus placebo, mediation analyses demonstrated that only 26–32% of the glycemic effects (HbA_1c and glucose) were attributable to weight loss in individuals with prediabetes or T2D (21).

Overall, the analyses support the concept of a pharmacologic weight loss strategy for preventing T2D, even in the setting of rigorous therapeutic lifestyle changes. As such, there is a critical need for studies that are specifically designed to assess this outcome. A recent international panel convened by the American Diabetes Association with representatives from multiple other expert groups published a consensus report that defined T2D remission as occurring when three criteria are met: 1) glucose control below the threshold accepted for clinical diagnosis (with the HbA_1c threshold <6.5% being the generally preferred method, when appropriate), 2) duration of glucose control below the diagnostic threshold for at least 3 months, and 3) being off of all glucose-lowering medication for sufficient duration to ensure cessation of the drug effect as well as to assess the effect of the absence of the drug on glucose control (22). The panel recommended assessing for T2D remission no sooner than 6 months after a lifestyle intervention, which is likely to require more time than either pharmacologic or surgical intervention. The panel stopped short of establishing criteria for “remission” of prediabetes, in part due to a lack of agreement on its definition (23), though a similar approach could be considered (Fig. 1). Moreover, since it is understood that normoglycemia and weight loss are not sustained following cessation of therapy, it would be important to assess much longer-term maintenance strategies, such as the benefits of ongoing or intermittent therapy, once initial treatment goals are achieved. Future studies should also include assessment of personalized medicine approaches to identify patients who are more likely to benefit from a given intervention (24), as well as the long-term impact on comorbidities and/or complications (4).