New Data Show Subset of Patients at Risk for Diabetes Despite Weight Loss

The American Diabetes Association highlighted the relationship between weight loss and diabetes prevention through a new long-term analysis of lifestyle interventions. Published in the journal Diabetes, the study reveals that for a specific subset of individuals at high risk for type 2 diabetes (T2D), even substantial and sustained weight loss may not be enough to prevent the progression of the disease.¹

This finding, stemming from the Tübingen Lifestyle Intervention Program (TULIP), suggests that the traditional one-size-fits-all approach to weight management may require a more nuanced, precision prevention strategy in clinical practice.^1,2

“We were particularly interested in whether individuals in risk clusters 3 and 5 differed from those in other clusters with regard to improvements in blood glucose levels and the prevention of type 2 diabetes,” Professor Norbert Stefan, MD, the lead author of the study and head of the department of pathophysiology of prediabetes at Helmholtz Munich, said in a news release.²

For pharmacists, who are often the first point of contact for patients seeking weight loss advice or managing prediabetes, these results underscore the complexity of metabolic health beyond the scale. The TULIP study followed 190 participants for nearly 9 years and utilized a classification system that divided high-risk individuals into 6 distinct pathophysiological clusters.^1,3

Researchers discovered that individuals in cluster 5—characterized by older age, higher body mass index, and severe insulin resistance—experienced a deterioration in blood glucose levels and a decline in insulin secretion despite maintaining an average weight loss of 8% over the follow-up period. Remarkably, 41% of these individuals developed T2D, a stark contrast to the 0% conversion rate in low-risk clusters who achieved similar weight loss.¹

The mechanisms driving this risk appear to be rooted in the presence of pronounced fatty liver disease. Evidence suggests that insulin resistance caused by a fatty liver, combined with the impairment of insulin secretion from pancreatic beta cells, creates a metabolic trajectory that is resistant to standard lifestyle changes. In cluster 5 individuals, high liver fat content was associated with a failure to improve insulin secretion, leading researchers to suggest that interventions specifically targeting liver fat might be more effective for this phenotype than generalized weight loss. Conversely, individuals in cluster 3, who are primarily beta-cell deficient, showed a much more favorable response to weight loss, with many reverting to normal glucose regulation.^1,2

“We were very surprised to find that, despite a large and sustained weight loss of 8% and after a very long follow-up period of 9 years, individuals in risk cluster 5 showed increasing blood glucose levels, declining insulin secretion, and a persistently high risk of type 2 diabetes,” Stefan said.²

This research adds a layer of depth to the broader clinical understanding of weight management, which has seen conflicting results in large-scale trials like Look AHEAD. Although that trial demonstrated that intensive lifestyle interventions improved various cardiovascular risk factors and led to partial remission of T2D in some patients, it failed to show a definitive reduction in major cardiovascular events. Pharmacists should note that although weight loss is unequivocally beneficial for improving quality of life, mobility, and physical function, its impact on long-term disease progression is highly dependent on an individual’s specific metabolic phenotype.³

As medication experts, pharmacists are well-positioned to help bridge the gap between these findings and patient care by considering the weight-related impacts of various glucose-lowering therapies. Current guidelines suggest that for patients where weight loss is a primary goal, certain classes like glucagon like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors may offer therapeutic advantages by promoting weight reduction alongside glycemic control.³

However, for high-risk phenotypes like cluster 5, these findings suggest that even pharmaceutical weight loss may need to be paired with more intensive or targeted strategies to truly mitigate diabetes risk. Ultimately, the goal is to transition toward a model of care where prevention is as personalized as the treatment of the disease itself.^1,2

READ MORE: Diabetes Resource Center

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REFERENCES

1. Meier CZ, Wagner R, Ganslmeier M, et al. Different Metabolic Responses to Long-term Weight Loss After Lifestyle Intervention Among Type 2 Diabetes Risk Clusters: Results From the TULIP Study. Diabetes. 2026;75(6):965-973. doi:10.2337/db25-0757

2. Not everyone benefits: diabetes risk persists despite long-term weight loss. News release. German Center for Diabetes Research. April 23, 2026. Accessed June 5, 2026. https://www.dzd-ev.de/en/article/nicht-jeder-profitiert-diabetes-risiko-trotz-langfristigen-gewichtsverlusts

3. Wilding JP. The importance of weight management in type 2 diabetes mellitus. Int J Clin Pract. 2014;68(6):682-691. doi:10.1111/ijcp.12384