Clinical Research Takes a Village: Paying Homage to the Unsung Members of the Team

Advancing the medical care of people takes a variety of discovery initiatives. An important component is the successful performance of clinical trials that advance our understanding and can change the approach to treatment, whether the results of the intervention(s) are positive or negative.

In the world of diabetes, since the early 1960s, we have witnessed clinical intervention studies in both type 1 and type 2 diabetes. In general, these have lasted from months to a few years. Many have fundamentally been for the development of new medications that have helped improve glycemic outcomes for people with diabetes, and these frequently have been sponsored by the pharmaceutical industry. On the other hand, federally funded studies have typically been focused primarily on nonglycemic outcomes and lasted years to even decades.

The longest study in the field of diabetes has been the Diabetes Control and Complications Trial (DCCT), which commenced recruitment in 1983 under the able leadership of Dr. Oscar Crofford and was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). In his role as chair of the National Commission on Diabetes, he was well positioned to advocate for the study and was chosen to lead what started as a feasibility study (1) and soon became a full-fledged clinical trial (2) that enrolled 1,441 participants and followed them for a mean of 6.5 years (range 3–9). At the time the study commenced, it was fervently debated whether the principal cause of long-term complications in people with type 1 diabetes was hyperglycemia or whether complications were the result of other unrelated factors such as genetic susceptibility. The results of the study were announced at the 53rd American Diabetes Association Scientific Sessions, held in Las Vegas in June 1993, and were published a few months later (3). The results emphatically demonstrated that glucose was the culprit. As of the writing of this editorial, per PubMed, this article has been cited nearly 27,000 times. The importance of the study cannot be underestimated, as it fundamentally changed our approach to treating diabetes.

Today, nobody thinks twice about using approaches to improve glucose control, with the ultimate goal being to lower the glycated hemoglobin (HbA_1c) to as close to normal as possible without excessive hypoglycemia. The basis for doing so is the DCCT! The results of the study demonstrated conclusively that in people with type 1 diabetes, intensified glycemic control achieved by multiple daily injections of insulin, along with home blood glucose monitoring up to seven times a day using glucose strips (versus conventional therapy), reduced the risk of developing retinopathy by 63%, albuminuria by 39%, and clinical neuropathy by 60% (3). These benefits came with a two- to threefold increase in severe hypoglycemia. Today, for many this approach to improving glycemic control is outdated, as advances in technology have occurred in leaps and bounds so that now people with diabetes and their health care team can choose from a variety of approaches, including automated insulin delivery devices and continuous glucose monitoring linked to cell phone technology. These technical advances may provide the same benefit but with a substantially reduced risk of hypoglycemia.

Following the announcement of the primary DCCT findings, the NIDDK wisely decided to fund a long-term observational follow-up of the study’s participants in the Epidemiology of Diabetes Complications (EDIC) study. With this follow-up, it has been reported that prior intensive control had beneficial effects that included not only a continued reduction in microvascular complications but also decreases in the risk of cardiovascular disease (4) and all-cause mortality (5). Another remarkable observation that gets less publicity is that the overall mortality in the DCCT/EDIC cohort that received intensive therapy was similar to that observed in the general population (6). Now entering its fifth decade, DCCT/EDIC continues to inform on and demonstrate the value of glycemic lowering in people with type 1 diabetes.

The success of most major studies is usually ascribed to the investigators and staff who work tirelessly out of the limelight to design, initiate, and execute the study per a well-developed protocol. They are then lauded for their achievements through presentations and publications that inform on the findings of the study and regularly result in changes in the practice of medicine and benefits for our patients. For all of this, we have the utmost respect and admiration for these dedicated teams.

However, behind the scenes of these rather public-facing events are the people who really allow the study to begin, occur, and ultimately enlighten us all. These are the study participants who sacrifice time and give indefatigably while at the same time accepting unknown risks. The risk may include being randomized to the placebo arm and thus missing the opportunity to benefit from a new therapy or being randomized to an intervention that could do more harm than good. It is the latter that the people who volunteered for the DCCT knowingly faced when they first enrolled in the study. At that time, the benefit of improved glycemic control was not clear, and some argued it was not likely to make a difference and could produce more harm because of the increased risk of hypoglycemia. Thus, the brave women and men who participated in the DCCT set out on a journey of exploration that in the world of diabetes could be seen as discovering new lands.

We dedicate this issue of Diabetes Care to the recognition of the contributions of all involved in the DCCT/EDIC over the last four decades. This month’s issue includes a special collection of five new articles with lessons for people with diabetes and their care team that arise from the dedication of everyone involved in the DCCT/EDIC. These articles bring the total to over 80 from this study that have been published in Diabetes Care, and they are freely available on the journal’s website at diabetesjournals.org/collection/2297/DCCT-EDIC-Special-Article-Collection. There is also a commentary from the leadership of the NIDDK that addresses the importance of the five new articles to our current knowledge and in some ways acts as a gratifying nod by the authors to those members of the institute who in prior years had the foresight to launch and continue this vital study. Further, two of the three leaders of the DCCT/EDIC over the past 40 years provide a brief history of the study for us to recall what many did not have the opportunity to witness.

To highlight the role of the DCCT/EDIC participants and our gratitude to them, we feature two additional items in this issue of Diabetes Care. The first is the cover, drawn by Pamela Kirton, a study participant from Minneapolis whose wonderful story about how she came to enroll in the DCCT is elaborated on in the About the Artist biography. The second is something the journal has never done before. As part of this special collection, we are featuring a collection of material developed specifically by the DCCT/EDIC leadership to recognize the 40th birthday of the study. This truly informative publication contains numerous quotes from participants on what the study has meant to them; three of these quotes are included at the end of this editorial. In partnership with the study’s leadership, we are delighted to give our readers access to this special piece of history and to let you learn more about the DCCT/EDIC, its meaning to its participants, and the value it has had for our whole community. It can be downloaded for free at diabetesjournals.org/collection/2296/DCCT-EDIC-Special-Article-Collection.

In closing, while the focus of this editorial and the special collection is on the DCCT/EDIC study and the critical role it played in advancing our understanding of diabetes, we also want to pay homage to all research participants, the unsung members of the teams in prior and current studies that are teaching us so much. Clinical research takes a village, but without every one of these dedicated research volunteers there would be no advancements, and the care of our fellow citizens would not improve. We appreciate you all and will remain eternally grateful to you for everything you have given and continue to give.