Type 2 diabetes (T2D) has historically been regarded as a chronic, irreversible disease. This conventional view has been challenged by growing evidence that lifestyle changes and surgical or medical interventions can achieve normoglycemia and, in some cases, even remission.

In 2021, four major societies issued a joint consensus statement defining remission in T2D as an A1c < 6.5% for 3 months after the cessation of glucose-lowering pharmacotherapy.

“We chose 6.5% because that is the threshold by which we define diabetes,” Amy Rothberg, MD, a coauthor of the consensus report, told Medscape Medical News.

“The concept and definition of remission were borrowed from other diseases, primarily cancer, and is defined as achieving not necessarily the complete absence of the disease but below the detectable limit of the disease,” said Rothberg, clinical professor of medicine, research professor of nutrition sciences, and director of the Weight Management Program at the University of Michigan, Ann Arbor, Michigan.

“Remission” isn’t the same as “reversal,” noted Scott Isaacs, MD, president of the American Association of Clinical Endocrinology and adjunct associate professor of medicine at Emory University, Atlanta.

“‘Remission’ refers to a reduction or disappearance of the signs and symptoms of a disease, but it doesn’t mean the disease is ‘cured,’” he told Medscape Medical News.

Rothberg added, “By the time people are diagnosed with type 2 diabetes, they already have a great magnitude of impairment and have lost beta-cell mass. Even if we can fully stop the progression of the disease — and the jury is still out on that — these patients aren’t going to recover those cells.”

Clear language is important, Isaacs said. “Referring to diabetes as ‘reversed’ can falsely reassure patients that they no longer need to monitor their health or sustain lifestyle changes.”

Weight loss is a major predictor of achieving remission as obesity contributes to insulin resistance and beta-cell decompensation. Patients with T2D and obesity are advised to lose at least 5% of their body weight, with ≥ 15% loss producing additional benefits.

BS has yielded dramatic improvements in glucose levels in patients with longstanding diabetes, driven largely by weight loss. The American Diabetes Association’s guidelines for obesity management for T2D recommend BS for patients with BMI ≥ 40 (or 27.5-32.4 in Asians) unable to maintain weight loss with nonsurgical interventions.

Numerous studies support the superiority of BS over conventional treatment in achieving diabetes remission. In the Swedish Obesity Subjects study, remission rates were eightfold higher at 2 years and threefold higher at 10 years compared with conventional treatment. Follow-up data from this study showed that after 2 years weight fell by 23.4% in the surgery group vs 0.1% in the control group, and after 10 years, weight was 16.1% below baseline in the surgery group but increased by 1.6% in the control group.

The benefits of BS extend beyond weight loss. T2D is an inflammatory disease and BS has been associated with anti-inflammatory effects. Benefits often appear soon after surgery, even before significant weight loss, suggesting that the effects cannot be attributed to weight loss alone.

Medications can also facilitate remission. Both SGLT-2 inhibitors and GLP-1 receptor agonists (GLP-1 RAs) induce significant weight loss, although GLP-1 RAs generally produce greater weight loss.

“A lot of the effects of modern pharmacotherapies are weight-dependent,” Rothberg commented. “As people lower their body fat, and fat is removed from the pancreas and liver, they feel better, improve their health, and hopefully reverse some of the pathophysiology.”

In one randomized study, pairing an SGLT2 inhibitor with a calorie-restricted diet led to remission in 44% of patients compared with 28% of those who received placebo.

GLP-1 RAs show similar potential. A recent study of over 14,000 adults (mean BMI, 32) evaluated four different definitions of remission, all requiring achieving an A1c of < 6.5% for ≥ 3 months:

Remission 1: No diabetes pharmacotherapy

Remission 2: GLP-1 RAs continued, all other diabetes medications stopped

Remission 3: No intensification of diabetes therapy from baseline

Remission 4: A1c target met, regardless of ongoing diabetes medication use

Remission occurred in 5.8%, 6.2%, 12.2%, and 18.3% of participants, respectively.

“This large real-world study demonstrated that remission of type 2 diabetes with GLP-1 RAs is achievable,” Isaacs summarized.

GLP-1 RAs also appear to exert anti-inflammatory effects in patients with T2D, according to a meta-analysis of over 4700 patients. In fact, GLP-1 RAs represent a “significant breakthrough” in anti-inflammatory therapy, offering novel treatment options that can contribute not only to diabetes remission but also to improvements in other conditions as well.

“The traditional thinking of type 2 diabetes is a one-way street — once you develop it, it continues to progress — hasn’t taken into account diet or lifestyle interventions,” said Vanita Rahman, MD, clinic director of the Barnard Medical Center and clinical instructor in medicine at the George Washington University School of Medicine, Washington, DC.

Rahman advocates a low-fat whole-foods plant-based (WFPB) diet, citing a growing body of evidence suggesting its benefits in weight loss and glycemic control.

In research conducted by her group, 58 patients with T2D completed a 12-week online program incorporating a low-fat WFPB diet without calorie restriction, in which participants maintained their pre-intervention medication and exercise practices.

Mean weight dropped by 3.7 kg, mean A1c fell by 0.6%, and 22% reduced diabetes medication doses.

“This study was conducted in a primary care setting, showing this type of intervention is feasible and efficacious in that setting,” Rahman told Medscape Medical News.

The effectiveness extends beyond weight loss, Rahman added. “Research has shown that diets high in fat contribute to insulin resistance, while lower-fat diets improve insulin sensitivity.” And WFPB diets have been shown to exert anti-inflammatory effects in T2D.

Rothberg agreed that lifestyle interventions work, pointing to the DiRECT trial, in which nearly half of intervention participants achieved remission at 1 year using a very low-calorie diet and structured refeeding. However, only about one quarter maintained remission without medication after 5 years.

Rothberg’s own trial of the REWIND program — a virtual, community-based weight management project — showed substantial and sustained weight loss (16% at 6 months and 14% at 18 months), and diabetes remission in 52% and 43% of participants with T2D at 12 and 18 months, respectively.

“People think lifestyle changes are an adjunct to pharmacotherapy, but it’s the other way around,” she said. “Pharmacotherapy, when used, should be the adjunct to lifestyle changes.”

Although many patients require and benefit from medications for weight loss and/or diabetes, “that doesn’t apply to everyone,” Rothberg said. She believes clinicians should invite patients to attempt lifestyle changes.

“Many professionals assume people would rather take a drug than change their behaviors. But I’m not sure all patients would feel that way, if given an effective lifestyle and behavioral change intervention.”

She advised clinicians to openly discuss the prognosis of diabetes with patients and their caregivers, as they would for any other serious disease, and tailor dietary guidance based on each individual’s needs, environment, and support system.

Such an approach, she said, can give patients the best shot at achieving and sustaining remission.

Rothberg was the site principal investigator for research funded by Boehringer Ingelheim and had a speaking engagement for Eli Lilly. Rahman reported being an employee of the Physicians Committee for Responsible Medicine, a nonprofit organization providing educational, research, and medical services related to nutrition. Rahman has authored several books on nutrition and reported receiving royalties from these sources. Isaacs reported being the president of AACE.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).