David M. Nathan: An Epic Investigator, An Epoch in Diabetes Care

David Nathan is internationally renowned for his stellar leadership in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded multicenter clinical trials testing the most pressing hypotheses in diabetes care. He joined the Diabetes Control and Complications Trial (DCCT) as a young clinical investigator, becoming the principal investigator at the MGH site in 1982, soon after joining the faculty. He then became the chair of the Publications and Presentations Committee in 1985 and brought his formidable writing skills to the group as the editor for DCCT publications. He ultimately led the long-term follow-up of the DCCT as the principal investigator of the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, partnering with John M. Lachin and the wonderful group at the George Washington University Biostatistics Center, with whom he would do so much excellent work over the following decades (including the Diabetes Prevention Program [DPP], Treatment Options for Type 2 Diabetes in Adolescents and Youth [TODAY] study, and Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study [GRADE]).

Diabetes Care readers do not need to be reminded that the DCCT definitively proved the glucose hypothesis that hyperglycemia causes microvascular complications in diabetes (2). EDIC has now followed participants for another 30 years, demonstrating the lasting benefit of initial tight glucose control on myriad outcomes, including cardiovascular disease, in type 1 diabetes (3,4). David and his close colleague and career-long research collaborator, Mary E. Larkin, have maintained close relationships with and cared for DCCT-EDIC participants for four decades, demonstrating what it means to have a true partnership with research participants. A model of clinical trial rigor and conduct, the DCCT remains one of the most influential clinical trials conducted in any field, as measured by citations and impact on clinical care and health.

David has also been a leader in clinical trials in type 2 diabetes. He chaired the DPP from 1994 to 2002. The landmark DPP trial demonstrated that, compared with placebo, lifestyle intervention targeting 7% weight loss reduced the incidence of diabetes by 58%, and metformin 850 mg twice daily reduced the incidence by 31%, over 2.8 years among individuals with impaired glucose tolerance (5). He then led the Diabetes Prevention Program Outcomes Study (DPPOS) for two decades. DPPOS demonstrated many other lasting benefits of the interventions, including a sustained benefit in diabetes prevention over time (6). The DPP has been disseminated and implemented in many formats, led by the Centers for Disease Control and Prevention National Diabetes Prevention Program (7), supported with reimbursement by the Centers for Medicare & Medicaid Services, and adapted for mHealth delivery. David was also a lead investigator in Look AHEAD (Action for Health in Diabetes) (8), the study that evaluated lifestyle intervention for cardiovascular risk reduction in type 2 diabetes, and the TODAY study, which compared the effectiveness of metformin alone with the addition of rosiglitazone or lifestyle intervention to metformin in youth with recently diagnosed type 2 diabetes (9).

David led the first American Diabetes Association (ADA) and European Association for the Study of Diabetes consensus algorithm on the management of hyperglycemia in type 2 diabetes in 2006 (10), and an update in 2009 (11); as thiazolidinediones met their Waterloo, and the first dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists were introduced, the need for a head-to-head comparison of the major classes of glucose-lowering medication to be used after metformin became clear. David then led the launch of one of the largest comparative-effectiveness trials in diabetes, GRADE (12).

Although comparative effectiveness is now a buzzword, most clinical trials of medications are placebo controlled. While a placebo control is crucial to demonstrate the efficacy of a new treatment, the question that patients and clinicians face is how to choose among different effective therapies. Most of David’s trials, including the ones mentioned above, have had a comparative effectiveness component, but GRADE was the first to compare what were then the four most commonly used glucose-lowering medication classes head-to-head. GRADE picked up where A Diabetes Outcome Progression Trial (ADOPT) left off, having evaluated the comparative effectiveness of rosiglitazone, glyburide, and metformin as initial glucose-lowering treatment over 4 years (13). The design of GRADE was reminiscent of the these studies and the hypertension arm of the long-term Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared chlorthalidone, amlodipine, and lisinopril (14). Like ALLHAT, GRADE, including only effective treatments, did not have dramatically different primary outcomes across treatment arms. However, the nuances and differences among treatments help to answer the question of which medication to use for which patient. GRADE demonstrated that early use of basal insulin was the most durable treatment to maintain HbA_1c <7%, was readily accepted by participants with the lowest discontinuation rate over time, and had very few side effects compared with the other medications, including low rates of hypoglycemia and weight gain. In addition, GRADE showed that liraglutide was associated with the lowest risk of a broad cardiovascular composite outcome in participants without established cardiovascular disease (15,16).

In addition to leading and participating in many of the landmark multicenter clinical diabetes trials of the past four decades, David has contributed to many other aspects of diabetes translational and clinical research, nationally and at MGH. Joseph Avruch, who led the MGH Diabetes Unit for nearly four decades, recalls David’s first years in diabetes research and the factors contributing to his early success:

Highlights of some of David’s other work are detailed below.

Building on his earlier work, David helped to standardize the HbA_1c assay and was a founding member of the National Glycohemoglobin Standardization Group. He demonstrated the value of the HbA_1c through the DCCT and multiple epidemiologic analyses. He led the A1C-Derived Average Glucose (ADAG) study to peg the HbA_1c to glucose levels, helping to establish the estimated average glucose (eAG) measurement (23). Ever the curious scientist, in recent years, he has also led a reevaluation of the subtleties and even pitfalls of HbA_1c as it relates to glucose values the continuous glucose monitoring (CGM) substudy of GRADE. This study is the largest study comparing CGM with HbA_1c and other glycated proteins in a diverse cohort and will help to disentangle many of the questions about discrepancies between HbA_1c and CGM-measured glucose values.

One of David’s early diabetes articles was a solo–first author 1982 publication demonstrating successful use of a continuous variable rate insulin infusion adjusted to meal size in four patients with “brittle,” previously uncontrolled, type 1 diabetes (20,24). The insulin pump studies, as with so many others he led, were conducted in MGH’s legendary Mallinckrodt General Clinical Research Center (GCRC) (25). Further (comparative effectiveness!) studies of injection versus pump therapy (20), implantable pumps (26,27), optimal medical oversight and diet for pumps (28,29), and, of course, insulin pumps in the DCCT followed. David’s insulin pump work came full circle when he mentored Steven Russell’s clinical research program developing the bihormonal bionic pancreas (30,31) in the very same GCRC where he had launched his own career.

If there was a “right-place-at-the-right-time” moment of his career, however, it would be David’s first-author paper with Svetlana Mosjov and Joel Habener published in 1992 in Diabetes Care. In “Insulinotropic Action of Glucagonlike Peptide-I--(7–37) in Diabetic and Nondiabetic Subjects” (32), they were the first to describe in humans that GLP-1-(7-37) indeed augmented insulin release, an effect that was attenuated at decreased glucose levels, and reduced postprandial glycemic excursions in the individuals with type 2 diabetes. He concluded, “Whether GLP-I-(7–37) is useful as a therapeutic medication in type II diabetes requires further investigation.” Understatement of the decade!

Space does not permit me to expand on David’s many early contributions to diabetes epidemiology as a coinvestigator on diabetes reports from the Framingham Heart Study (33–36), Nurses’ Health Study (37), and many other clinical epidemiology projects, including those of his many mentees. He has written innumerable book chapters, edited many journals, and has served as the Editor-in-Chief of Diabetes and Endocrinology for UpToDate, where his expertise, rigor, and careful editing have reached and improved the knowledge and care of clinicians everywhere. And of course, he is a popular teacher among students, trainees, and practicing clinicians, both at Harvard Medical School and as a visiting professor nationally and internationally.

Similarly, while his visiting professorships, awards, and honors are too numerous to mention, he has been recognized widely, including with the ADA’s Outstanding Service Award (1987), election to the American Society for Clinical Investigation, ADA’s Charles Best award (as part of the DCCT in 1994), ADA’s Outstanding Physician-Clinician Award (2002), and ADA’s Outstanding Achievement in Clinical Diabetes Research Award (2015, inaugural award). A listing of many, but not all, of his articles, awards, and honors can be found in his online curriculum vitae (38).

Beyond David’s scientific accomplishments, he stands out to me as someone unique among academics of his stature for his tendency to speak truth to power. He is an advocate for his patients, mentees, and important causes in medicine and society. He is the person the ADA taps nearly every year to take the “unpopular” debate position; not infrequently, he is asked to argue the side opposed to pharmaceutical interests. To understand this part of David’s persona, it may help to learn a bit about his background.

David grew up in New York, the oldest of three brothers. His father Ira, a good-humored scientist, was the director of the Berg Cardiac Research Laboratory at New York University School of Medicine. When I met Ira Nathan, I recognized the same friendly, smiling eyes as his oldest son. David’s mother, Rhoda Nathan, was an English professor whose specialty was George Bernard Shaw, political activist, satiric dramatist, and Nobel laureate. Shaw seems to have cast a long shadow over the Nathan family. Weaned on witticisms, David and his mother traded banter until her death in 2021. All of David’s colleagues can recall his frequent trips to New York to care for her, and the many times in recent years when he briefly interrupted a meeting to take one of her calls, patiently joking with her to help her manage a difficult moment.

At Amherst College, David double majored in biology and English, going on to Mt. Sinai School of Medicine, followed by residency at the Peter Bent Brigham Hospital and fellowship in endocrinology at MGH. I once asked Joe Avruch why David had remained in his job, given that he had so many opportunities to “advance” to positions of administrative leadership. Referring to David’s persistent curiosity and enthusiasm for clinical research, he replied, “David still likes to play in the sandbox.” His twin passions of science and English allowed him not only to pursue the most important questions but also to communicate his findings so effectively.

In 1983, David’s mother fixed him up with her friend’s daughter, Ellen Lubell, a beautiful, funny, and brilliant attorney who specialized in nonprofit and copyright law. They married and remained in Boston, returning to New York frequently to see family and traveling widely around the world with their sons, Josh and Ben. Growing up in a household committed to social justice, both of their children have gone on to careers with major civic impact: Josh worked on a wide range of curricula and educational ventures in the U.S., Middle East, and Africa and is now an attorney working in social finance. Ben is a policy analyst and advisor to utilities and cities on energy affordability and equity. David never brags about his wonderful family or his children’s accomplishments, but I cannot recall seeing him happier than when he described his children’s weddings.

Despite a level of success that would convert many into establishment stalwarts, David remains at heart an unreconstructed sixties liberal, advocating for those less powerful than himself. This very clearly comes through his care of patients. He remained the primary care physician for most of his patients until the practice could no longer support it, and he keeps his pager signed in unless he is traveling internationally. He exhorts the fellows at our annual clinic orientation that we at the MGH Diabetes Center are not “sugar dentists” but, rather, take on all of the issues that contribute to health and well-being in people with diabetes, from management of medical comorbidities, to mental health evaluation and care, to grappling with barriers to diabetes self-management. When he attends on the endocrinology or inpatient diabetes service, he identifies and tries to remedy disparities and systems issues related to substandard care. He is also a master clinician, having seen and done it all.

David’s propensity to help others is also evident in his mentorship. He invites many people into his big tent, giving them the space to grow and develop. There is no one better to help refine the message of a talk, paper, or grant application, but he does not micromanage. Moreover, David does not just mentor carbon copies of himself (and not just because there aren’t any!). He is a true humanist, who meets people where they are, connects to the individual ideas and needs of the mentee, and moves forward from there. Thus, a remarkably diverse group of individuals have benefitted from his support: from nurse and dietitian investigators, whose careers he has advanced in a system geared toward physician investigators, to physicians currently in clinical research and clinical practice, to luminaries such as Gerry Shulman, David Altshuler, and Jose Florez.

Finally, his inclusive nature comes through in his social and professional interactions. At a conference, you are more likely to find David talking to postdocs in the back corner of the poster hall than at a fancy insider dinner. At office parties, David hobnobs with the medical assistants, front desk staff, and research coordinators. At the holidays, David ensures that staff gift plans are in place and adequately funded. And he shows up wearing his crazy holiday sweater, given to him by MGH DCCT participants at the end of the DCCT.

David, who never stopped playing in the sandbox, has always been a great supporter of junior investigators. Students, residents, fellows, postdocs—he will meet with anyone, bat around their idea, and punch it up in the process. My own initial connection with him occurred when I ran into him on MGH wards and told him I was interested in diabetes research. He said, “Great, join us!” and that was it.

His sandbox has been the clinical research center. He established the MGH Diabetes Clinical Research Center in 1983. He was the Director of the Mallinckrodt General Clinical Research Center at MGH from 1990 to 2008 and stewarded its transition to the National Institutes of Health’s Clinical and Translational Science Awards era as Director of the MGH Clinical Research Center of the Harvard Catalyst. Dismayed by the National Institutes of Health’s defunding of the clinical research centers, David and his near namesake, David G. Nathan, pediatric hematologist and President Emeritus of the Dana-Farber Cancer Institute, penned a “Eulogy for the Clinical Research Center” in the Journal of Clinical Investigation in 2016 (39). This brave op-ed described the history and value of the CRCs as well as their current importance to scientific and medical discovery and unsparingly reviewed the events leading to their defunding. Emile Zola would be proud.

Despite his modesty, it is fair to say that while many people were in the same place at the same time as he was, it was what David Nathan did at those moments that mattered. David helped patients, supported colleagues, and immeasurably advanced diabetes care over the course of four decades in which the experience of treating, and, more importantly, living with diabetes has been transformed. While leading national research efforts, he founded the collaborative Diabetes Research Center and led MGH’s GCRC, creating the infrastructure for clinical research and fostering the careers of so many others. Woven throughout all of this, of course, is David’s wonderful sense of humor. I can imagine him reading this heimishe festschrift and exclaiming, “I am not dead yet!” Fortunately, this is very true, and this invited piece is somewhat premature. I think we can expect many more years of David just “happening to be there” when something cool happens in diabetes, dispensing great wisdom to colleagues and mentees, and speaking up for what matters in the world.

Acknowledgments. The author gratefully acknowledges the contributions of Joseph Avruch for his description of David Nathan’s early career and comments on an earlier draft and Mary Larkin for comments on the draft and sharing photographs.

Duality of Interest. D.J.W. reports serving on Data Monitoring Committees for Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.