On March 10, 2025, leadership of a research study known as the Diabetes Prevention Program Outcomes Study (DPPOS) was notified that the grant supporting the study had been terminated. The DPPOS and its predecessor the Diabetes Prevention Program (DPP) have studied a group of patients since the inception of the DPP in 1996. More than 3000 participants were enrolled, selected because they were at high risk for developing diabetes. The studies have successfully tested strategies to reduce the risk of diabetes and have continued to study the same group of participants for nearly 30 years, looking at a variety of health outcomes in this aging cohort. The most recent focus is Alzheimer’s disease and dementia.
This is a multicenter study, involving 30 institutions across the USA. Due to the way NIH structures this type of grant, the funding for the entire study apparatus is managed through a central grant recipient. In recent years Columbia University has become the funding center. Columbia receives the funds from NIH and distributes these to the various centers.
No official justification for the defunding has been given, but it was part of a sweeping cancellation of federal grants to Columbia University. It is speculated that Columbia was singled out because of the Administration’s grievance regarding student protests and antisemitism on campus. Because Columbia happens to be the funding hub, the result is a de facto defunding of the entire DPPOS study.
Diabetes and its complications
If I had the power to wave a wand and eliminate one disease from the face of the earth, diabetes would be a top candidate. Alzheimer’s disease would also be on the short-list. Diabetes is responsible for a great deal of premature death and disability–most notable are heart disease, kidney disease, stroke, and blindness. There is a strong link between Type 2 diabetes and dementia.
Recent CDC data (2021) estimated that 38.4 million (11.6%) Americans have diabetes. It is not only devastating for health, it is expensive. The costs of diabetes (including medical costs plus lost work and wages) cost $413 billion in 2022. The prevalence of diabetes is growing. Nearly 98 million Americans have prediabetes.
Every medical specialty sees and treats diabetic complications. As an ophthalmologist, I dealt with the devastation caused by diabetic retinopathy. Much of what we know, and much of the progress we have made in treating diabetes and managing complications are due to NIH sponsored studies. These studies are referred to by awkward initialisms like: DCCT, EDIC, and ETDRS. They are canonical in the medical literature and have been profoundly impactful in the day to day medical care of people with diabetes.
The Diabetes Prevention Program
Improving our treatment of chronic disease is important, but prevention is more impactful, both clinically and financially. Enter the Diabetes Prevention Program (DPP). The DPP was a randomized clinical trial conducted between 1996 and 2001 at 27 clinical sites in the US. 3,234 participants were enrolled. Study participants met predefined criteria identifying as high-risk for development of Type 2 diabetes. Participants were randomized to one of three groups (cut and pasted from the NIH website) below.
- Lifestyle Change Group – Group participants joined a DPP Lifestyle Change Program that provided intensive training. Participants tried to lose 7 percent of their body weight and maintain that weight loss by eating less fat and fewer calories and exercising 150 minutes per week. Researchers met with participants individually at least 16 times in the first 24 weeks, and then every 2 months with at least 1 phone call between visits.
- Metformin Group – Group participants took 850 mg of metformin* twice a day and were provided standard advice about diet and physical activity.
- Placebo Group – Group participants took a placebo twice a day instead of metformin and were provided standard advice about diet and physical activity.
*Metformin is a first line medication for the treatment of Type 2 diabetes and one of the most prescribed medications in the world.
Results of DPP
The DPP identified two strategies for at-risk patients to reduce their risk of progressing to Type 2 diabetes. Compared to the placebo group, both intervention groups demonstrated a reduced risk of progression to Type 2 diabetes. After 3 years, the Lifestyle Change Group lowered their risk by 58%. The metformin group lowered their risk by 31%. These are large treatment effects. Given the magnitude of diabetes in the US, any incremental reduction in the incidence of new cases represents a huge public health benefit.
The Diabetes Prevention Program Outcomes Study
The Diabetes Prevention Program Outcomes Study (DPPOS) is an extension of the DPP. The study has proceeded in phases, focusing on different health outcomes as the study population ages. Phase 1 demonstrated that lifestyle modification and metformin continued to protect against the development of type 2 diabetes after 10 years. Later phases have focused on other health outcomes including cancer, heart disease, stroke, nerve disease, kidney disease, and retinopathy. The DPP and DPPOS have been highly productive and highly prolific, producing more than 200 publications.
There is a strong link between Type 2 diabetes and Alzheimer’s. The DPPOS is a unique resource to study this association. The most recent phase of the study has added dementia, including Alzheimer’s disease. The current phase began in 2022 and is scheduled through 2027.
Consequences of defunding DPPOS
Last month I wrote an SBM article discussing the abandonment of more than 30 clinical trials due to defunding of USAID. I discussed the direct and collateral effects of the sudden, unplanned termination of these studies. These are equally applicable to the sudden unplanned defunding of the DPPOS.
I will discuss the consequences on 3 levels: the practical, the personal, and the scientific.
The practical
Managing a clinical research study with the size and complexity of DPPOS is a major feat. Thousands of patients seen at dozens of institutions across decades creates a logistical nightmare. As a result, studies like this have a complex infrastructure. Study protocols must be written, communicated, and implemented. They are periodically amended. Participants are recruited, consented, and followed. Visits must be carefully coordinated to conform to specified timelines.
Sites stay in contact with participants. Missed visits must be noted and rescheduled. Participants must be notified of changes in the protocols. Data are collected and communicated to coordinating centers, all constrained to protect participant privacy. Labs are collected analyzed and similarly forwarded. Records must be stored in compliance with local and national regulations. Sites are audited. Data are collected, collated, and analyzed. Papers are written. Study committees meet. Study-wide meetings must be organized.
Suddenly cutting off funding, without a plan, effectively ends the study. The sites may have enough funds to continue operations for a while, but institutions cannot continue to assign personnel to studies without expectations that they can pay them. Employees understand the writing on the wall and will move on to more secure projects. Unless funding can be reestablished, day to day operations will cease and decades of accumulated data will be wasted. The most recent phase exploring Alzheimer disease and dementia will likely be abandoned, and funds already invested will be wasted.
The personal
Research participants are volunteers. In order to qualify for a study, they must endure a screening process to determine eligibility. If eligible, they go through a rigorous informed consent process. If they accept the details of consent, and agree to the terms of the study, they can enroll. As a study participant they agree to adhere to the study protocol, which often involves visits, procedures, and investigations far in excess to what they would experience in “usual care.” There is no certainty that they will personally benefit from their participation.
Participants are free to withdraw from a study at any time. Because DPP and each phase of DPPOS are considered separate studies, participants were re-consented for and re-enrolled for each study. 85% of eligible patients transitioned from DPP to DPPOS, considering this was a separate study, this is excellent patient retention, a tribute to the trust and to the strength of the relationship among the study participants, the investigators, and the rest of the study staff.
Why do participants volunteer for studies? Motivations are varied. Many participants have expressed to me their hope that information learned from the study will be beneficial to others. To remain connected to a study and to a group of researchers for decades reflects a powerful connection and commitment to the project. At this point participants have little expectation of personal benefit. Many persevere due to a to a valid sense that they are part of a team and a hope that their participation will benefit others. The relationship between participants and researchers is a powerful ingredient to the success of long-term studies like DPPOS. Regarding study staff, José Luchsinger, one of the principal investigators at Columbia noted:
“They are the connection with the study participants…if we lose that connection, it would be very difficult to resume the study in the future.”
The premature termination of this study limits the likelihood that the study will produce additional data that will improve health. Imposing such limits is a snub to the altruistic motivation of the volunteers who have been faithful to the study for decades.
One long-term study participant expressed pride in contributing data to guide professionals in advising patients with diabetes. Faced with the discontinuation of the study: “Honestly, I wanted to cry,” she said.
The Scientific
DPP and the various phases of DPPOS were not launched arbitrarily. They were evaluated on merit and priority. They were approved by appropriate ethical review committees. Ultimately, they were awarded because they were expected to answer important questions and to improve the outcomes of people with and at risk for diabetes. They were approved by appropriate ethical review committees.
There can be justification for interrupting a study early. A study may be paused if the interim results are definitive; if the risks of continuing the study are too great; or if it becomes clear that the study has little to no potential to reach a meaningful conclusion. Often contingencies for these interruptions are pre-specified in the study protocol and based on the advice of an independent review committee which has access to the data. In each of these examples, certain aspects of the study may be stopped or modified BUT, the study participants are not abandoned. They will often be debriefed on the reasons for termination or modification of the protocol. I am aware of no scientific or ethical justification offered for the defunding/termination of DPPOS.
The DPPOS is not just a series of research projects, it is an ecosystem. It is a collection of experts teaming with a group of volunteers who have been studied for decades. These participants have been studied using standardized assessments on a defined schedule. With a resource like this it is possible to look forward and to look backward to answer important questions and to generate hypotheses for future research. The longer funding is withheld, the more will be lost, and the more difficult it will be to resume. At some point there will be a loss of too many participants, too many investigators, and too much data to resurrect the study. The opportunity cost of dismantling this resource is impossible to calculate.
Backlash
The deconstruction of DPPOS seems particularly ironic considering current Health and Human Services secretary Robert F. Kennedy Jr.’s assertion that current research priorities are insufficiently addressing chronic illness.
An editorial in Medscape referred to the cancellation as a “Colossal Waste.”
The DPPOS investigators, The Endocrine Society and the American Diabetes Association have all appealed to promptly resume funding of DPPOS.
The Chairpersons of the Congressional Diabetes Caucus have written a letter to the Secretary of HHS and the acting Director of the NIH urging them to take action to reinstate funding of DPPOS.
David M. Nathan, MD, Chair of the DPPOS Research Group has written a letter explaining the value of DPPOS, urging reinstatement ASAP, He concludes with this paragraph:
Any continued interruption threatens the stability of the staff, the connection to the participants who have been a part of this work for more than 30 years, and the potential to salvage the scientific integrity of the study. If this decision is not reversed, it will undermine our nation’s best opportunity to uncover the root cause of Alzheimer’s and Dementia, waste taxpayer’s investments, and work against the Administration’s stated goal of Making America Healthy Again. We urge you to take immediate action to call for reinstatement of this funding to the study sites across the country through whatever means necessary.
It is wasteful and sad that a resource like DPPOS is being starved to death without justification.