ORLANDO, Florida — What to prioritize first in managing early diabetes? That was the question debated on an expert panel at the American Diabetes Association (ADA) 84th Scientific Sessions, with impassioned responses ranging from a plea to “treat obesity first,” to a James Carville–inspired counterpoint of “it’s the glucose, stupid.”
With a focus on preventing complications and inducing remission rounding out the four positions argued, Session Moderator Ravi Retnakaran, MD, of the University of Toronto, in Toronto, Ontario, Canada, noted that the options reflect the tricky choices clinicians treating patients with diabetes are pressed to make on a daily basis.
“In clinical decision-making [for early diabetes], we are faced with weighing each of these variables for the individual patient, and while all are good options, strong arguments can be made for prioritizing each — with the potential of each choice to influence or improve all of the others,” Retnakaran told Medscape Medical News.
Making the obesity first argument, Ania M. Jastreboff, MD, PhD, an associate professor and director of the Yale Obesity Research Center at Yale School of Medicine, in New Haven, Connecticut, noted the striking statistic that nearly 90% of people with type 2 diabetes have overweight or obesity and discussed the ever-expanding data showing the benefits of drugs including glucagon-like peptide 1 (GLP-1) receptor agonists not just in weight loss but also in kidney, cardiovascular, and, as presented at the meeting, even sleep apnea improvement.
She contrasted the experiences of two patients with obesity: One treated for the obesity upon type 2 diagnosis — who had a quick normalization of lipids and hypertension soon after the obesity treatment — and the other presenting after 10 years with type 2 diabetes — who was on therapy for hypertension and hyperlipidemia but not for obesity and whose diseases were not as easily treated by that point.
“Why are we treating all the downstream effects and we’re not treating the disease that is potentially the root cause of all these other diseases?” Jastreboff said.
Arguing in favor of focusing on complications, Roopa Mehta, MD, PhD, with the Department of Endocrinology and Metabolism at INCMNSZ, Mexico City, Mexico, made the case that stakes don’t get any higher in diabetes than when it comes the looming threat of potentially fatal complications.
Acute myocardial infarction, stroke, amputation, and end-stage renal disease are all on the list of unwanted outcomes and need to be considered even in the earliest stages, as data show early onset type 2 diabetes is linked to life expectancy.
“The main goal of management has always been to prevent complications,” she noted. Citing ADA guidelines, Mehta underscored the benefits of first- and second-line therapy of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and GLP-1 receptor agonists for most patients.
Discussing the priority of putting patients into disease remission, Roy Taylor, MD, a professor of medicine and metabolism at Newcastle University and Newcastle Hospitals NHS in Newcastle upon Tyne, England, and author of the book Life Without Diabetes, focused on an evidence-based alternative to achieving remission — a nonpharmacologic approach that avoids costly and sometimes inaccessible drugs.
In the intervention, described in the DiRECT randomized trial and subsequently in the UK National Health Service Type 2 Diabetes Path to Remission Program, patients with overweight or obesity were placed on a highly restrictive diet of just 800-900 calories a day for 12-20 weeks, followed by maintenance for 12 months, and they not only achieved weight loss but also achieved diabetes remission, in some cases long-term.
Acknowledging that “this is not for everyone,” Taylor asserted that “we have to realize there is a substantial minority of people who want to be healthy but who don’t want to be medicalized,” he said.
“They want their health, and they can do extremely well.”
In taking his self-titled “it’s the glucose, stupid” stand, David M. Nathan, MD, of the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, in Boston, cited extensive evidence showing that early intensive blood glucose control with treatment including sulfonylureas, insulin, or metformin significantly reduced the risk for complications in type 2 diabetes 15 or more years later, including renal failure, blindness, amputation, and myocardial infarctions, in addition to a reduction in diabetes-related death.
“In many of these studies, you saw the benefit even in the setting of weight-gain,” Nathan underscored.
He further noted the “sobering” findings of the Look AHEAD study, which had to be stopped due to futility when an intensive lifestyle/weight loss intervention showed no significant benefits in terms of cardiovascular disease in people with type 2 diabetes at a median follow-up of 9.6 years.
Ultimately, “diabetes, type 1 and type 2, remains a gluco-centric disease,” Nathan asserted. “Hyperglycemia is the only universal link between all forms of diabetes and mortality, and the long-term complications of diabetes are intimately associated with hyperglycemia.”
The ensuing panel discussion did not fail to deliver in delving into key areas of contention, particularly in terms of GLP-1 treatment.
Regarding a lack of data on the potential long-term effects of GLP-1s: “Yes, there are a huge number of studies [on GLP-1 receptor agonists], but they are, in general, over short periods of time and driven by pharma, who get in and get out as quickly as they can and have little in the way of interest to do comparative effectiveness studies,” Nathan argued.
“Meanwhile, this is like the crack cocaine of medications — patients have to stay on it for a lifetime or they will regain the weight — are you concerned at all about a lifetime of exposure to GLP-1 [drugs]?” he asked the panel.
Jastreboff responded that the first GLP-1 receptor agonist medications were approved in 2005, nearly 20 years ago, by the US Food and Drug Administration.
“Do I think we need long-term lifetime data? Absolutely,” she said. “We need to do our due diligence, we need to be careful, we need to monitor patients, and when and if there are signals, we need to follow them.”
What about the notorious gastrointestinal side effects of the drugs? “A majority of them are mitigated by slow up-titration,” Jastreboff noted.
“If patients have nausea, I do not go up [in dose]. I invite patients to tell me if they’re having vomiting because I don’t want anybody to have it, and I can count on one hand how many of my patients do.”
Metha added the concern that as the drugs’ popularity soars, “a lot of doctors don’t know when they need to put the brakes on [weight coming off too quickly].”
She underscored that “we are not treating obesity for weight loss or for cosmetic reasons — this is about optimizing health.”
Jastreboff noted that in her practice, “I down-titrate if they’re losing weight too quickly.”
“If the patient is losing more than 1% per week of their body weight, then I slow down to make sure they’re getting the nutrients that they need, that they have enough energy to exercise, and that they’re prioritizing protein and fruits and vegetables in their diet.”
“We just need to go slow, and yes, we need to follow them long term,” she said.
Chiming in from the audience, Julio Rosenstock, MD, a recognized thought-leader in type 2 diabetes, offered his own take on the issues, describing Taylor’s very low–calorie diet suggestion as “not realistic” and Nathan’s glucose-first argument to be “stuck in the past.”
Based on modern-day evidence, “there is no reason on earth to start [diabetes treatment] with only metformin,” asserted Rosenstock, who is director of the Velocity Clinical Research center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas.
“We need to start at the very least with metformin and a sodium-glucose cotransporter 2 (SGLT2) inhibitor from day 1, and then, if it’s affordable and there is access, with a GLP-1 receptor agonist,” he said.
“There is nothing better these days than those agents that consistently have shown a reduction of cardiovascular events and slowing of kidney disease progression.”
Overall, however, “I think you are all right,” he added, a sentiment shared by most.
Noting that the discussion as a whole represents a virtual sea change from the evidence-based options that would have been discussed only a decade ago, Retnakaran summed up his take-home message: “Stay tuned.”
“You could easily see things changing in the next decade to come as we get more data and evidence to support what we ultimately should prioritize an early type 2 diabetes, so this is an exciting time.”
Retnakaran’s disclosures included research and/or consulting relationships with Novo Nordisk, Boehringer Ingelheim, Novartis, Sanofi, and Eli Lilly. Jastreboff’s disclosures included relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terms Pharmaceutical, Weight Watchers, and Zealand Pharmaceuticals. Roopa had relationships with Novo Nordisk, Boehringer Ingelheim, Amgen, AstraZeneca, Eli Lilly, Silanes, and Sanofi. Taylor received lecture fees from Novartis, Lilly, Abbott, and Nestle Health and research funding from Diabetes UK and is an advisor to Fast800. Rosenstock reported relationships with Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Oramed, Structure Therapeutics, Novartis, Novo Nordisk, Pfizer, Ragor, and Sanofi. Nathan had no disclosures to report.
